PATENTABILITY SEARCH-Quick(Detailed Report)

SAMPLE REPORT

Client Ref. No.: XXXXXXXXXX TPSF Ref. No: XXXXXXXXXX

For: Client

May 11, 20XX

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Client Logo

Thank you for allowing us to conduct your search!

Your search fell into one of the categories highlighted below. Please read the description of the category before taking (or not taking) any further steps.

Category 1: A thorough search was conducted, but no relevant patents were found. No further recommendations are made.

Category 2: A thorough search was conducted, and a few close references were found. These are categorized in three primary groups. The “Relevant” group discloses all the features explicitly, the “Related” group appears to disclose some of the features but not all, and the “Interesting” group that appear to be related in some way but are mostly provided to illustrate surrounding technologies. (Note that the “Related” group may also include some “Relevant” group patents. Category 3: A thorough search was conducted, and a few references were found. These are categorized in three primary groups. The “Related” group appears to disclose some of the features but not all, and the “Interesting” group that appear to be related in some way but are mostly provided to illustrate surrounding technologies. (Note that the “Related” group may also include some “Relevant” group patents). The references in this category should be reviewed carefully by the client for relevance, as the inference drawn by us is subjective to our understanding and is done to provide the best case scenario, the client may interpret the references in a different way.

Category 4: A thorough search was conducted and a few references were also identified but a further search in a different jurisdiction is recommended for potentially better results..

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Table of Content

1 SEARCH OVERVIEW & BACKGROUND.................................................................................42 SEARCH SCOPE....................................................................................................................5

2.1 Objective of the Search................................................................................................5

2.2 Assumptions.................................................................................................................5

2.3 Data Sources.................................................................................................................5

3 METHODOLOGY..................................................................................................................64 SEARCH STRATEGY..............................................................................................................7

4.1 Term Set.......................................................................................................................7

4.2 Search Strings...............................................................................................................9

4.3 Relevant Classes Identified.........................................................................................10

4.4 Glossary of Specific Search Operators Used...............................................................10

5 RELEVANCE CRITERIA........................................................................................................115.1 Relevant Results.........................................................................................................11

5.2 Related Results...........................................................................................................11

5.3 Interesting Results......................................................................................................11

6 SEARCH RESULTS...............................................................................................................126.1 Key Features to be mapped........................................................................................12

6.2 Summary of Search Results........................................................................................13

6.3 TPSF Summary............................................................................................................14

6.4 Detailed Analysis of Search Results............................................................................15

6.4.1 Relevant Patent Results....................................................................................15

6.4.2 Related Patent Results......................................................................................23

6.4.3 Relevant Non-Patent Results............................................................................26

6.4.4 Interesting Results.............................................................................................28

7 NON-DISCLOSURE.............................................................................................................298 DISCLAIMER...................................................................................................................... 29

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1 SEARCH OVERVIEW & BACKGROUND

Client asked TPSF to conduct a Prior Art Search to identify patent and non-patent references that could affect the patentability of the invention related to Camel Antibodies.

TPSF has gone through the invention and developed the following understanding:

A Phage-displayed library of dromedary camel single heavy domain antibodies (sdAbs) which selectively bind to Helicobacter pylori urease (HPU).

From the said library, four highly reactive sdAbs were selected, sequenced and grafted into a heavy chain antibody Fc region sequence of IgG2 isotype. The full heavy chain antibodies are active against gastritis and are resistant to stomach acidity and temperature.

The product is intended to be used in oral therapy of human gastritis caused by Helicobacter pylori in different dosage formulas.

TPSF carried out the search as per the following variant chosen by the client:

VARIANT COVERAGE SEARCH LANGUAGE

QuickPatent Search in US, EP and WO [All Full Text]

EnglishNon-Patent Search

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2 SEARCH SCOPE

2.1 Objective of the Search

The objective of our search was to identify reference(s) disclosing:

Production of recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.

Recombinant Full Camel Heavy Chain Antibodies with selective binding to Helicobacter pylori urease.

Use of Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.

2.2 Assumptions

Assumptions1. Questel Orbit database was used for conducting Patent searches.2. Google, Scholar, Science-Direct, PubMed and PubChem were used for conducting non-patent searches.3. The term 'Patent' has been used as a collective term for Patents and Published Applications.4. The comprehensiveness of this search has been governed by the upper cap on the effort to be invested.5. This search has been carried out as per our Quick Variant and covers US, EP and WO jurisdictions using keywords in English language.

2.3 Data Sources

Patent Sources Non-patent SourcesFor Bibliographic Data (including title, abstract):Questel OrbitEspacenetGoogle Patents

For Non-Patent Searches:Google ScholarScience-DirectPubMedPubChem

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3 METHODOLOGY

The following methodology was adopted for performing the Patentability Search:

Methodology

Task Details OutputStep I Understanding

TPSF developed a thorough understanding of the technology area and client’s requirements to prepare a strategy for the search.

A preliminary strategy for the search was prepared including keyword-based search, citations search, assignee/inventor name search

Step II aKeyword-based Patent Searching

TPSF generated a list of keywords to be used for conducting the patent and non-patent search, as per the preliminary search strategy. Further, the list of search strategy was used to perform patent searches on Questel Orbit patent databases. The patents obtained from the search were analysed to identify relevant/related patents.

A set of relevant/related patents

Step II bClass-based Searching

TPSF conducted searches using relevant classes, such as IPC/CPC/ECLA etc., with broad keywords to identify additional patents relevant to the domain.

A set of relevant/related patents

Step II cPatent Citations Searching

TPSF conducted Spider citation analysis for relevant/related patents obtained from the steps II a & b.

A set of relevant/related patents

Step IIIAssignee Based Searching

TPSF conducted searches using potential assignees in the field of the study.

A set of relevant/related patents

Step IVNon-Patent Searching

The search strings prepared for the patent search were modified to adapt to syntax of non-patent searches. Searches were carried out on different non-patent databases to obtain a list of non-patent references matching the keyword criteria. These non-patent references were screened on the basis of free-information (mostly abstract).

A set of relevant/related non-patent references

Step VReport Preparation

An MS Word document containing the project overview, search strategy, relevance criteria and the results was prepared.

MS Word Report

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4 SEARCH STRATEGY

The following search strings, some combinations and/or some syntactical variations of them were used to conduct searches on Questel Orbit to extract patents for analysis or extract other relevant information to assist in searching.

Similarly, syntactical variations of these strings were run on non-patent databases as well.

4.1 Term Set

Keyword Based Search

Term Set Keywords

Single Heavy Domain Antibody Term Set

(Single D heavy D domain D (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR (single D domain 3D (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR sdAbs OR Nanobody OR ((antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+)) 5D (single W monomeric W variable W antibody+ W domain+)) OR (Camel+ W Single 2W Domain W Antibod+) OR (camel+ W antibod+) OR (camel+ W heavy 2W chain W variable 2W domain W (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR (heavy W chain W (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR ((“VHH” OR VHsquare+) 2D (fragment+ OR antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR (single W domain W heavy W chain W (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+)))

Full Size Heavy Chain Antibody Term Set

((immuno OR immune) W globulin+) OR (HcAb) OR (full W size W heavy W chain W (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR (heavy W chain W (antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+))) OR Antibod+ OR ((recombinant OR engineer+) D (Antibod+ OR immunoglobulin OR ((immuno OR immune) W globulin+)))

Gastritis Term Set

Gastritis OR ((inflammat+ OR irritat+ OR erosion OR acid+ OR burn+ OR damag+) 5D (stomach OR (gastric W mucosa) OR (gastrointestinal W tract) OR GIT OR abdomen+ OR abdomin+)) OR gastroenteritis OR ((abdomen+ OR abdomin+ OR stomach OR belly) 2D (pain OR upset)) OR indigestion OR dyspepsia OR ((Peptic OR gastric OR stomach OR duodenal) 2D ulcer+)

Helicobacter Pylori Urease Term Set

(((Helicobacter W pylori+) OR (“H” D Pylori+)) D urease) OR ((Helicobacter OR Campylobacter) W pylori+) OR (“H” D Pylori+) OR Helicobacter+ OR (Helicobacter W urease) OR (((Gram W negative) OR microaerophilic) D bacteri+) OR Helicobacteraceae OR Proteobacteria OR Epsilonproteobacteria OR Campylobacterales OR urease

Oral Route Term Set((oral+ OR mouth OR buccal+ OR sublingual+) 2D (route OR administer+ OR administr+ OR dose OR therap+ OR treat+ OR deliver+)) OR Pill+ OR tablet+ OR capsule+

IgG2 Term Set IgG2 OR (“Ig” W “G2”) OR ((immunoglobulin+ OR ( immun+ W

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globulin+)) W (“G2” OR (gamma OR Angebot OR gamme ))) OR (recombinant W "IgG") OR (Immunoglobulin+ W “G” W “2” ) OR (gamma 2D immunoglobulin+) OR (("IgG" W “2”) W (isotype W antibod+)) OR igG

Dromedary Term Set

dromedar+ OR ((Arabian OR Indian) W camel+) OR (Camelus W dromedar+) OR camel+ OR Camelidae OR Camelus OR (Camelus W aegyptiacus W Kolenati) OR (africanus W Gloger) OR (arabicus W Desmoulins) OR (dromas W Pallas) OR (dromos W Kerr) OR (ferus W Falk) OR (lukius W Kolenati) OR (polytrichus W Kolenati) OR (turcomanichus) OR (vulgaris W Kolenati)

Grafting Term SetGraft+ OR insert+ OR fus+ OR combin+ OR integrat+ OR transplant OR implant+ OR transfer+ OR join+ OR attach+ OR engraft+ OR fix+ OR conjoin+ OR hybrid+

Antibody Term Set

+protein+ OR +peptid+ OR antibod+ OR immunoglobulin+ OR ((immuno OR immune) W globulin+) OR monoclonal OR polyclonal OR ((mono OR poly) W clonal) Or Ig OR ab OR abs OR mab OR mabs OR iga OR igg OR iggs Or igd OR igds OR ige OR iges OR igm OR igms OR Fab OR Fabs OR Fv OR Fvs OR scFv OR scFVs Or “VH” OR “VL” OR (variable W (heavy OR light)) OR (single W chain W variable) Or ((heavy OR light) W chain+) OR HcAB OR HcABs OR (antigen W (bind+ OR specifi+)) OR CDR OR CDRs OR (complement+ W determin+ W region+ ) OR CDR1 OR CDR2 OR CDR3 OR CDR1s OR CDR2s OR CDR3s OR ((variable OR hypervariable) W region+) OR slg OR mlg OR slgs OR mlgs OR ((gamma OR mu OR alpha OR epsilon OR delta Or kappa OR lambda) W chain+)

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4.2 Search Strings

S. No. Search String

1Title, Abstract, Claims(Single Heavy Domain Antibody P Full Size Heavy Chain Antibody) AND (Gastritis) AND (Helicobacter Pylori Urease)

2Title, Abstract, Claims(Single Heavy Domain Antibody P Full Size Heavy Chain Antibody) AND (Grafting) AND (IgG2)

3Title, Abstract, Claims(Single Heavy Domain Antibody P Full Size Heavy Chain Antibody) AND (Gastritis) AND (Oral Route)

4Title, Abstract, Claims(Single Heavy Domain Antibody P Full Size Heavy Chain Antibody) AND (Dromedary)

5Title, Abstract, Claims (Single Heavy Domain Antibody) AND (Full Size Heavy Chain Antibody) AND (Helicobacter Pylori Urease)

6Full Patent Specification(Antibody) AND (Dromedary) AND (Helicobacter Pylori Urease)

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Full Patent Specification(Antibody) AND (Gastritis)ANDAny Classification C07K-016/12

8 Any Classification C07K-2317/00

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Full Patent Specification(Full Size Heavy Chain Antibody) AND (Helicobacter Pylori Urease) AND (Dromedary)ANDAny Classification C07K-016/00

10 Citation Searching

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4.3 Relevant Classes Identified

The following Classes were used in combination with the term sets provided above:

Class Definitions

C07K 16/12 CHEMISTRY; METALLURGY --> Immunoglobulins, e.g. monoclonal or polyclonal antibodies --> against material from bacteria

C07K 2317/00 CHEMISTRY; METALLURGY --> PEPTIDES-->Immunoglobulins specific feautures

C07K-016/00CHEMISTRY; METALLURGY --> Immunoglobulins, e.g. monoclonal or polyclonal antibodies

4.4 Glossary of Specific Search Operators Used

Operators Definitions

+ Any number of characters

nW Search for words in the same sentence and appearing within n words of one another, in the written order. If n is omitted, the number defaults to one

nD Search for words in the same sentence and appearing within n words of one another, but in either order. If n is omitted, the number defaults to one

S Search terms occur in the same sentence

P Search for words in the same paragraph

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5 RELEVANCE CRITERIA

References identified from the search were manually analyzed and tagged as relevant, related and interesting. Provided below is the description of each category:

5.1 Relevant Results

Those patent and non-patent references were considered as Relevant that disclosed: The production of recombinant Heavy Chain Antibodies; wherein, the process comprises

selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.

Use of recombinant Full Camel Heavy Chain Antibodies with selective binding to Helicobacter pylori urease for the treatment of gastritis in human by oral administration.

5.2 Related Results

Those non-patent references were considered as Related that disclosed: The single domain antibodies or nanobodies derived from camelid that are linked to Fc

portion of IgG2. Delivery of the single domain antibodies or nanobodies prepared to the gastrointestinal

tract by oral administration.

5.3 Interesting Results

Those patents and Non patent references that appeared to be potentially related; however, these could not be categorized as relevant or related and thus were marked as Interesting Results. Note that this list has just been provided to give you an idea of what else exists in the art and is not meant to be comprehensive.

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6 SEARCH RESULTS

6.1 Key Features to be mapped

The following pointers have been identified based on the features of the client disclosure. All the relevant and/or related results identified in the search are mapped on these key features to properly depict their significance.

1. Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.

2. Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

3. Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.

For Summary of Search Results, please click here.

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6.2 Summary of Search Results

The results of the search have been presented in the report below. The analysis below provides bibliographic details of the identified references and relevant excerpts from the identified references. The Patent number / Non-patent title provided is also hyperlinked to the complete document, which includes all the figures and text.

You can access the weblink of the document by clicking over the Patent number / Non-patent title. (If you are viewing in MS Word, then you’ll need to press your control key while you click.)

S. NO. PATENT / PUBLICATION

KEY FEATURE 1 KEY FEATURE 2 KEY FEATURE 3

Patent Results

1 WO2013166594A1 Yes Yes Yes

2 WO2006056306A2 Yes Yes Yes

3 WO2004041867A2 Yes Yes Yes

4 US2013136744A1 Yes Yes Yes

5 US20100136018A1 Yes No Yes

Non Patent Result

6 Non-Patent Result 1 Yes Yes Yes

For Key Feature details, please click here.

LEGENDS:

For References:This result is identified as Relevant

This result is identified as Related

For Key Feature Mapping:This feature is not explicitly disclosed but can be inferred

This feature is explicitly disclosed

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6.3 TPSF Summary

The following search summary is provided to give the client a bird’s eye view of the search. The inferences drawn by us are subjective to our understanding and are done to provide the best case scenario; the client may interpret the references in a different way.                                                  The focus of the search was on identifying the documents explicitly disclosing the production of recombinant Heavy Chain Antibodies, wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.

For this, we identified 2 potentially relevant documents WO2013166594A1 and WO2006056306A2. One of these documents discloses the heteromultimer comprising single domain antigen-binding construct and an immunoglobulin heterodimer Fc region, said single domain antigen-binding construct is a camelid nanobody (V[h]H). These heteromultimers of the invention are used to treat or prevent various bacterial and autoimmune diseases. While the other document discloses a system for delivering antibodies to the gastrointestinal tract comprising heavy chain immunoglobulins of the VHH i.e. heavy chain antibodies derived from camelids.

Further, we performed searches focusing on recombinant full camel heavy chain antibodies that have selective binding to Helicobacter pylori urease and are useful in the treatment of gastritis in human by oral administration. We came up with four potentially relevant documents WO2004041867A2, US2013136744A1. These documents disclose use of therapeutic molecules comprising polypeptide construct having at least one single domain antibody that is a Camelidae VHH and are selective against Helicobacter pylori for use in the treatment, prevention and/or alleviation of gastritis. The document describes binding of VHH domains with the Fc domain, but the Fc domain of IgG2 isotype is not explicitly disclosed.

During these searches, we also identified a related document i.e. US20100136018A1. This document discloses nanobodies derived from camel that are linked to the Fc domain of IgG2. These nanobodies can be used for oral therapeutic administration into the gastrointestinal tract. However, the document does not explicitly mention that nanobodies are specific to Helicobacter pylori urease.

We also identified one potentially relevant Non-Patent Result 1 disclosing single-variable domain of heavy chain antibody against recombinant UreC. The isolated nanobody can specifically detect and bind to UreC and inhibit urease activity. This nanobody could be a novel class of treatment measure against H. pylori infection i.e. gastritis.

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6.4 Detailed Analysis of Search Results

6.4.1 Relevant Patent ResultsThis is the list of most relevant hits available in the art for the given invention identified in the search. Please note that the focus was on identifying the closest hits and not on identifying all the hits comprehensively. Accordingly, the list might not be comprehensive and there might be more documents that are similar (i.e., having the equal or slightly lower relevance) to the documents listed below. Also, the search is restricted to English language and US, EP and WO jurisdictions.

1. WO2013166594A1 TPSF comments: This prior art discloses the isolated heteromultimers comprising single domain antigen-binding construct attached to at least one monomer of a heterodimer fc region. These heteromultimers of the invention are used to treat or prevent various bacterial and autoimmune diseases.

TitlePublication Date Filing Date

Priority Date

Inventor/ Author Assignee

HETEROMULTIMER CONSTRUCTS OF IMMUNOGLOBULIN HEAVY CHAINS WITH MUTATIONS IN THE FC DOMAIN

14 NOV, 13 10 MAY, 13 10 MAY, 12 SPRETER ET AL.

ZYMEWORKS INC

AbstractProvided herein are isolated heteromultimers comprising: at least one single domain antigen-binding construct attached to at least one monomer of a heterodimer fc region; wherein the heterodimer fc region comprises a variant ch3 domain comprising amino acid mutations that promote the formation of said heterodimer with stability comparable to that of a native fc homodimer; and wherein said isolated heteromultimer is devoid of immunoglobulin light chains and optionally devoid of immunoglobulin ch1 region. These novel molecules comprise complexes of heterogeneous components designed to alter the natural way antibodies behave and that find use in therapeutics.Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.Claims:1. An isolated heteromultimer comprising: at least one single domain antigen-binding construct and an immunoglobulin heterodimer Fc region, said immunoglobulin heterodimer Fc region comprising two monomeric Fc polypeptides, wherein the single domain antigen-binding construct is attached to one monomeric Fc polypeptide; wherein the heterodimer Fc region comprises a variant CH3 domain comprising amino acid mutations that promote the formation of said heterodimer Fc region with stability comparable to a native homodimeric Fc region; and wherein said isolated heteromultimer is devoid of immunoglobulin light chain and immunoglobulin first constant (CH1 ) region.

6. The isolated heteromultimer according to any one of claims 1 to 5, wherein the single domain antigen binding construct is selected from single domain antibodies (sdAb or VH), camelid nanobodies (V[h]H), cartilaginous fish (V[NA]R), SH3-derived fynomers, and

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fibronectin-derived binding domains.

7. The isolated heteromultimer according to any one of claim 1 to 6, wherein the single domain antigen-binding construct is a camelid nanobody (V[h]H).

43. The isolated heteromultimer according to any of Claims 1-42 comprising a Fc construct based on a type G immunoglobulin (IgG).

44. The isolated heteromultimer according to Claim 43, wherein said IgG is one of lgG1, lgG2 lgG3 and lgG4.KEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

Description:In one embodiment, the single domain antigen-binding construct is one that has a neutralizing activity on the target antigen. The term "neutralizing activity," as used herein in the context of a single domain antigen-binding construct, refers the ability of the single domain antigen-binding construct to block binding of a cognate ligand to the target antigen.

In another embodiment, the target cell is one that is activated or amplified when a subject is suffering from an infection with a pathogenic organism, such as bacteria or fungi.

TPSF Comments: As described in the document the antibody construct is used to target bacteria. But, it does not mention explicitly about Helicobacter pylori urease.KEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.Description:In one embodiment, the heteromultimers are used to treat infections of pathogenic organisms, such as bacteria or fungi.

Examples of inflammatory disorders which can be prevented, treated or managed in accordance with the methods of the invention include, but are not limited to, asthma, encephilitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergic disorders, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation resulting from chronic viral or bacterial infections.

Heteromultimers of the invention can also be used to reduce the inflammation experienced by animals, particularly mammals, with inflammatory disorders.Accordingly, compositions designed for oral, lingual, sublingual, buccal and intrabuccal administration can be made without undue experimentation by means well known in the art, for example, with an inert diluent or with an edible carrier.

TPSF Comments: As described in the document the antibody construct is used to treat the inflammatory disorders resulting from bacterial infection. Though, it doesn’t not mention about gastritis.

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2. WO2006056306A2 TPSF comments: This prior art discloses the delivery system comprising the heavy chain immunoglobulins or VHH or VNAR type, or domain antibodies (dAbs) for use in the management of infections, in particular of the gastrointestinal tract.

TitlePublication Date Filing Date

Priority Date

Inventor/ Author Assignee

HEAVY CHAIN AND DOMAIN ANTIBODIES

01 JUN, 06 03 NOV, 05 25 NOV, 04 FRENKEN ET AL

UNILEVER NV,

AbstractThe present invention relates to heavy chain immunoglobulins or fragments thereof of the vhh or vnar type, or domain antibodies (dabs) of the heavy or light chains of immunoglobulins or fragments thereof, suitable for use in the management of infections, in particular of the gastrointestinal tract. The present invention also relates to a delivery system comprising these heavy chain immunoglobulins or functional fragments thereof of the vhh or vnar type, or domain antibodies (dabs) of the heavy or light chains of immunoglobulins or fragments thereof, and hosts comprising expression vectors encoding for these heavy chain immunoglobulins or functional fragments thereof of the vhh or vnar type, or domain antibodies (dabs) of the heavy or light chains of immunoglobulins or fragments thereof. The invention also relates to food products and pharmaceutical preparations comprising the delivery system, and methods for the preparation of food products according to the invention.Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.Claims:1. A delivery system for delivering antibodies to the GIT comprising heavy chain immunoglobulins of the VHH or VNAR type or domain antibodies (dAbs) of the heavy or light chains of immunoglobulins or fragments thereof wherein the immunoglobulins or fragments thereof are active in the gut.

4. The delivery system as claimed in claim 1 comprising a micro-organism transformed with a gene encoding the heavy chain immunoglobulins of the VHH or VNAR type or domain antibodies (dAbs) of the heavy or light chains of immunoglobulins or fragments thereof.

5.The delivery system of claim 4 wherein the heavy chain immunoglobulins of the VHH or VNAR type or domain antibodies (dAbs) of the heavy or light chains of immunoglobulins or fragments thereof are expressed and/or secreted in the gut.

6. The delivery system of claim 5 wherein the immunoglobulins or fragments thereof are heavy chain antibodies derived from camelids, preferably llama heavy chain antibodies.

Background:Heavy chain antibodies constitute about one fourth of the IgG antibodies produced by the camelids, e.g. camels and llamas (Hamers-Casternian C, et al. (1993)). These antibodies are

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formed by two heavy chains but are devoid of light chainsKEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

Description:[0108] Immunoglobulins or fragments thereof have the following characteristics: i) They show good binding affinity and the desired inhibition functionality under the conditions present in the GIT; and ii) They have good proteolytic stability in that they are stable against degradation by proteolytic enzymes.

[0125] The present application is applicable to the management of enteropathogenic micro- organisms in general. Preferably, the invention is directed to the management of enteropathogenic viruses and/or enteropathogenic bacteria. Management is understood to include therapy and/or prophylaxis.

[0126] Enteropathogenic bacteria may include, for example, Salmonella, Campilobacter, E.coli or Helicobacter. Enteropathogenic viruses may include, for example, Noro virus

TPSF Comments : As described in the document, the antibody is used for the management of Helicobacter. But, it does not mention explicitly about Helicobacter pylori urease.KEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.Abstract:The present invention relates to heavy chain immunoglobulins or fragments thereof of the VHH or VNAR type, or domain antibodies (dAbs) of the heavy or light chains of immunoglobulins or fragments thereof, suitable for use in the management of infections, in particular of the gastrointestinal tract.

TPSF Comments: As described in the document, the delivery system has been used for the management of infections related to GIT, but it doesn’t explicitly mention about the oral administration of the antibodies.

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3. WO2004041867A2 TPSF comments: This prior art discloses the administration of therapeutic molecules comprising of polypeptide construct having at least one single domain antibody that is a Camelidae VHH. These single domain antibodies are directed against Helicobacter pylori for use in the treatment, prevention and/or alleviation of disorders relating to irritation of the stomach wall and gastritis.

Title Publication Date

Filing Date Priority Date

Inventor/ Author

Assignee

METHOD OF ADMINISTERING THERAPEUTIC POLYPEPTIDES, AND POLYPEPTIDES THEREFOR

21 MAY, 04 07 NOV, 03 10 JAN, 03 SILENCE ET AL

VAN BERGEN EN HENEGOUWEN PAUL,ABLYNX

AbstractThe invention relates to a method suitable for administering protein therapeutic molecules orally, sublingually, topically, intravenously, subcutaneously, nasally, vaginally, rectally or by inhalation so as to avoid inactivation, by using vhh polypeptides derived from camelidae antibodies. The invention further relates to the said therapeutic molecules. The invention furthers a method for delivering therapeutic molecules to the interior of cells. The invention further relates to anti-IgE therapeutic molecules.Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.Description:Another embodiment of the present invention is a method for delivering an anti-target compound to a subject for the treatment of a disorder without being inactivated by administering thereto a polypeptide construct comprising one or more single domain antibodies directed against said target.

Another embodiment of the present invention is a polypeptide construct as described above, wherein at least one single domain antibody is a humanized Camelidae VHH.

Any of the VHHs as used by the invention may be of the traditional class or of the classes of human-like Camelidae antibodies. Said antibodies may be directed against whole target or a fragment thereof, or a fragment of a homologous sequence thereof. These polypeptides include the full length Camelidae antibodies, namely Fc and VHH domains, chimeric versions of heavy chain Camelidae antibodies with a human Fc domain.

TPSF Comments: The document describes binding of VHH domains with the Fc domain, but it doesn’t explicitly mention about the Fc domain of IgG2 isotype.KEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

Description:Another embodiment of the present invention is a method as described above or polypeptide construct as described above wherein said target is any of antigen of Helicobacter pylori,

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antigen of Mycobacterium tuberculosis, antigen of influenza virus.

In one embodiment of the invention is a polypeptide construct comprising at least one single domain antibody directed against H. pylori, said construct and inhibits the enzymatic function of urease. Since single domain antibodies, in particular VHHs have the specific characteristic to occupy enzymatic sites, selected VHHs would inhibit the enzymatic activity and neutralize the virulence of a H. pylori infection.KEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.Description:One aspect of the invention is a polypeptide construct comprising one or more single domain antibodies directed against Helicobacter pylori for use in the treatment, prevention and/or alleviation of disorders relating to irritation of the stomach wall and gastritis, wherein said polypeptide construct is administered orally, sublingually, topically, intravenously, subcutaneously, nasally, vaginally, rectally or by inhalation, but preferably orally.

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4. US2013136744A1 TPSF comments: This prior art discloses the administration of therapeutic molecules by using VHH polypeptides derived from Camelidae antibodies. The polypeptide construct can be used to target against Helicobacter pylori for the treatment of gastritis.

TitlePublication Date

Filing Date

Priority Date

Inventor/ Author Assignee

METHOD OF ADMINISTERING THERAPEUTIC POLYPEPTIDES, AND POLYPEPTIDES THEREFORCAMELIDAE ANTIBODIES AGAINST IMMINOGLOBULIN E AND USE THEREOF FOR THE TREATMENT OF ALLERGIC DISORDERS

30 MAY, 13

7 FEB, 2013

8 NOV, 02 SILENCE ET AL

VAN BERGEN EN HENEGOUWEN PAUL ,ABLYNX

AbstractIn one aspect, the invention relates to a method suitable for administering protein therapeutic molecules orally, sublingually, topically, intravenously, subcutaneously, nasally, vaginally, rectally or by inhalation so as to avoid inactivation, by using VHH polypeptides derived from Camelidae antibodies. The invention further relates to the said therapeutic molecules. The invention further a method for delivering therapeutic molecules to the interior of cells. The invention further relates to anti-IgE therapeutic molecules.In one aspect, the present invention relates to a method wherein an immunoglobulin single variable domain (such as a Nanobody) and/or construct thereof are absorbed in pulmonary tissue. More particularly, the invention provides systemic delivery of an immunoglobulin single variable domain and/or construct thereof via the pulmonary route.Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.Abstract:In one aspect, the invention relates to a method suitable for administering protein therapeutic molecules orally, sublingually, topically, intravenously, subcutaneously, nasally, vaginally, rectally or by inhalation so as to avoid inactivation, by using VHH polypeptides derived from Camelidae antibodies.

Claims:1. Method of delivering an effective amount of an immunoglobulin single variable domain and/or construct thereof to a human; wherein said immunoglobulin single variable domain and/or construct thereof is directed against at least one antigen; and wherein the method comprises the step of administering said immunoglobulin single variable domain and/or construct thereof to the pulmonary tissue.

Description:[0147]Any of the VHHs as used by the invention may be of the traditional class or of the

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classes of human-like Camelidae antibodies. Said antibodies may be directed against whole target or a fragment thereof, or a fragment of a homologous sequence thereof. These polypeptides include the full length Camelidae antibodies, namely Fc and VHH domains, chimeric versions of heavy chain Camelidae antibodies with a human Fc domain.

TPSF Comments: The document describes binding of VHH domains with the Fc domain, but it doesn’t explicitly mention about the Fc domain of IgG2 isotype.KEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

Description:[0227]A non-limiting example of a therapeutic target against which a polypeptide construct of the invention may be used is Helicobacter pylori, which is a bacterium that lives in the mucus which coats the lining of the human stomach and duodenum. The normal human stomach has a very thin layer of mucus that coats the whole of its inside surface. This mucus has a protective role, acting as a barrier between the acid in the stomach and the sensitive stomach wall. H. pylori acts as an irritant to the lining of the stomach, and this causes inflammation of the stomach (gastritis). ,In one embodiment of the invention is a polypeptide construct comprising at least one single domain antibody directed against H. pylori, said construct and inhibits the enzymatic function of urease. Since single domain antibodies, in particular VHHs have the specific characteristic to occupy enzymatic sites, selected VHHs would inhibit the enzymatic activity and neutralize the virulence of a H. pylori infection.KEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.Description:In another aspect of the invention is a polypeptide construct comprising at least one single domain antibody directed against H. pylori, said construct inhibiting the adhesion of the bacteria to the stomach wall so preventing irritation of the stomach wall and gastritis. ,One aspect of the invention is a polypeptide construct comprising one or more single domain antibodies directed against Helicobacter pylori for use in the treatment, prevention and/or alleviation of disorders relating to irritation of the stomach wall and gastritis, wherein said polypeptide construct is administered orally, sublingually, topically, intravenously, subcutaneously, nasally, vaginally, rectally or by inhalation, but preferably orally.

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6.4.2 Related Patent Results

This is the list of most related hits available in the art for the given invention identified in the search. Please note that the focus was on identifying the closest hits and not on identifying all the hits comprehensively. Accordingly, the list might not be comprehensive and there might be more documents that are similar (i.e., having the equal or slightly lower relevance) to the documents listed below. Also, the search is restricted to English language and US, EP and WO jurisdictions.

5. US20100136018A1 TPSF comments: This prior art discloses nanobodies linked to the Fc domain of IgG2. These nanobodies can be used for oral therapeutic administration into the gastrointestinal tract.

Title Publication Date

Filing Date Priority Date

Inventor/ Author

Assignee

ANTI-FC-RECEPTOR SINGLE DOMAIN ANTIBODIES (NANOBODIES-TM) AND THERAPEUTIC USE

3 JUN, 10 20 DEC, 07 20 DEC, 06 DOLK EDWARD, ET

AL

ABLYNX

AbstractThe present invention relates to amino acid sequences that are directed against (as defined herein) receptors for proteins with an immunoglobulin fold (Fc receptors), as well as to compounds or constructs, and in particular proteins and polypeptides, that comprise or essentially consist of one or more such amino acid sequences. The invention also relates to nucleic acids encoding such amino acid sequences and polypeptides; to methods for preparing such amino acid sequences and polypeptides; to host cells expressing or capable of expressing such amino acid sequences or polypeptides; to compositions, and in particular to pharmaceutical compositions, that comprise such amino acid sequences, polypeptides, nucleic acids and/or host cells; and to uses of such amino acid sequences or polypeptides, nucleic acids, host cells and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes, such as the prophylactic, therapeutic or diagnostic purposes mentioned herein.Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.BSUM[0105]Again, such Nanobodies may be derived in any suitable manner and from any suitable source, and may for example be naturally occurring VHH sequences (i.e. from a suitable species of Camelid) or synthetic or semi-synthetic amino acid sequences, including but not limited to "humanized" (as defined herein) Nanobodies, "camelized" (as defined herein) immunoglobulin sequences (and in particular camelized heavy chain variable domain sequences), as well as Nanobodies that have been obtained by techniques such as affinity maturation (for example, starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, veneering, combining fragments derived from different immunoglobulin sequences, PCR assembly using overlapping primers, and similar

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techniques for engineering immunoglobulin sequences well known to the skilled person; or any suitable combination of any of the foregoing as further described herein.

[1191]According to one specific aspect of a polypeptide of the invention, one or more Nanobodies of the invention may be linked (optionally via a suitable linker or hinge region) to one or more constant domains (for example, 2 or 3 constant domains that can be used as part of/to form an Fc portion), to an Fc portion and/or to one or more   antibody   parts, fragments or domains that confer one or more effector functions to the polypeptide of the invention and/or may confer the ability to bind to one or more Fc receptors. For example, for this purpose, and without being limited thereto, the one or more further amino acid sequences may comprise one or more CH2 and/or CH3 domains of an antibody, such as from a heavy chain antibody (as described herein) and more preferably from a conventional human 4-chain antibody; and/or may form (part of) and Fc region, for example from   IgG   (e.g. from IgG1,   IgG2 , IgG3 or IgG4), from IgE or from another human lg such as IgA, IgD or IgM.KEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.

XKEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.BSUM[0022]The amino acid sequences and polypeptides of the invention could also be used to enhance the transport or transcytosis of compounds such as proteins or polypeptides (for example, of Nanobodies or ( single )   domain   antibodies) across biological membranes or cell layers, such as for example across an epithelial layer (such as the lining of the gastrointestinal tract, so as to make a compound delivered to the gastrointestinal tract -- e.g. by oral administration

[1308]Thus, the amino acid sequences, Nanobodies and polypeptides of the invention may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the amino acid sequences, Nanobodies and polypeptides of the invention may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the amino acid sequence, Nanobody or polypeptide of the invention. Their percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of the amino acid sequence, Nanobody or polypeptide of the invention in such therapeutically useful compositions is such that an effective dosage level will be obtained.[1310]Preparations and formulations for oral administration may also be provided with an enteric coating that will allow the constructs of the invention to resist the gastric environment and pass into the intestines. More generally, preparations and formulations

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for oral administration may be suitably formulated for delivery into any desired part of the gastrointestinal tract. In addition, suitable suppositories may be used for delivery into the gastrointestinal tract.

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6.4.3 Relevant Non-Patent Results

This is the list of most relevant hits available in the art for the given invention. Please note that the focus was on identifying the closest hits and not on identifying all the hits comprehensively. Accordingly, the list might not be comprehensive and there might be more documents that are similar (i.e., having the equal or slightly lower relevance) to the documents listed below. Also, the search is restricted to English language and US, EP and WO jurisdictions.

6. Non-Patent Result 1 TPSF comments: This prior art discloses a single-variable domain of heavy chain antibody against recombinant UreC. The isolated nanobody can specifically detect and bind to UreC and inhibit urease activity. This nanobody could be a novel class of treatment measure against H. pylori infection.

TitlePublication Date

Journal Details (publication volume, page number etc.)

Inventor/ Author

Affiliation

A NOVEL NANOBODY AGAINST UREASE ACTIVITY OF HELICOBACTER PYLORI.

03 APR, 13 VOLUME 17, ISSUE 9, PAGES E723-E728.

ARDEKANI ET AL DEPARTMENT OF BIOLOGY, FACULTY OF BASIC SCIENCE, SHAHED UNIVERSITY, TEHRAN, IRAN.

AbstractBackground: Helicobacter pylori infection is associated with gastritis and in some cases with gastric and duodenal ulcers and even adenocarcinoma. Antibiotic therapy has significant limitations, such as the high cost and the emergence of antibiotic-resistant strains, generating the need for new treatments. The administration of antibody against H. pylori is a new effective therapeutic strategy. In this study, we successfully developed a single-variable domain of heavy chain antibody against recombinant UreC.Methods: A VHH phagemid library was constructed from immune camel heavy chain antibodies. The nanobodies were displayed on M13 phage. Library selection was performed against UreC recombinant protein. A specific single-variable domain of heavy chain antibody against UreC was screened in five rounds of panning. The nanobody with the highest score in the phage ELISA was selected for soluble expression. The nanobody was purified with a nickel–nitrilotriacetic acid (Ni–NTA) column and confirmed with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Affinity, specificity, and urease inhibitory properties of the nanobody were assayed.Results: Here we showed the isolation and purification of a specific nanobody with high affinity against UreC recombinant protein that can inhibit urease activity.Conclusions: The isolated UreC nanobody can specifically detect and bind to UreC and inhibit urease activity. This nanobody could be a novel class of treatment measure against H. pylori infection.

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Key Feature MappingKEY FEATURE 1: Process for producing recombinant Heavy Chain Antibodies; wherein, the process comprises selecting, sequencing and grafting of dromedary camel derived sdAbs into heavy chain antibody Fc region sequence of IgG2 isotype.Abstract:A VHH phagemid library was constructed from immune camel heavy chain antibodies. The nanobodies were displayed on M13 phage. Library selection was performed against UreC recombinant protein. A specific single-variable domain of heavy chain antibody against UreC was screened in five rounds of panning. The nanobody with the highest score in the phage ELISA was selected for soluble expression. The nanobody was purified with a nickel-nitrilotriacetic acid (Ni-NTA) column and confirmed with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Affinity, specificity, and urease inhibitory properties of the nanobody were assayed.KEY FEATURE 2: Said Recombinant Full Camel Heavy Chain Antibodies have selective binding to Helicobacter pylori urease.Abstract:The isolated UreC nanobody can specifically detect and bind to UreC and inhibit urease activity. This nanobody could be a novel class of treatment measure against H. pylori infection.KEY FEATURE 3: Use of said Recombinant Full Camel Heavy Chain Antibodies for the treatment of gastritis in human by oral administration.Background: Helicobacter pylori infection is associated with gastritis and in some cases with gastric and duodenal ulcers and even adenocarcinoma. Antibiotic therapy has significant limitations, such as the high cost and the emergence of antibiotic-resistant strains, generating the need for new treatments. The administration of antibody against H. pylori is a new effective therapeutic strategy. In this study, we successfully developed a single-variable domain of heavy chain antibody against recombinant UreC.

Abstract:The administration of antibody against H. pylori is a new effective therapeutic strategy. In this study, we successfully developed a single-variable domain of heavy chain antibody against recombinant UreC

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6.4.4 Interesting Results

This list is just indicative in nature to give you some idea of what else is available in the art. Note that the list is not meant to be comprehensive.

1. WO2013038203A1

Title Publication Date

Filing Date Priority Date

Inventor/ Author

Assignee

THERMOSTABLE ASSAY REAGENTS

21 MAR, 13 14 SEP, 12 14 SEP, 11

SUTTON, JOHN MARK;

SKIPPER, PHILIP JAMES

ALISTER

HEALTH PROT AGENCY;

SUTTON JOHN MARK;

SKIPPER PHILIP JAMES

ALISTERAbstractThere is provided a single-chain fusion protein comprising :(i)a thermostable kinase and(ii)a single-domain antibody or single-domain antibody fragment. There is also provided a method of preparing a single-domain antibody or single-domain antibody fragment, the method comprising :(i) expressing the single- domain antibody or antibody fragment as a single-chain fusion protein with a thermostable kinase, in a host cell such as E.coli; and (ii)purifying the fusion protein from the cytoplasm of the host cell.

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