obviousness of biologics inventions: strategies for...
TRANSCRIPT
Obviousness of Biologics Inventions:
Strategies for Biologics Claims in the U.S.,
Europe and China
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THURSDAY, SEPTEMBER 5, 2019
Presenting a live 90-minute webinar with interactive Q&A
Bryan C. Diner, Partner, Finnegan Henderson Farabow Garrett & Dunner, Washington, D.C.
Dr. Hazel Ford, European Patent Attorney, Mathys & Squire, London
Simon Tianle Luo, Attorney, Wu Feng & Zhang, Beijing, China
Carla Mouta-Bellum, Ph.D., Partner, Arrigo Lee Guttman & Mouta-Bellum, Washington, D.C.
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Strafford Webinars, September 5, 2019
Carla Mouta-Bellum
Arrigo, Lee, Guttman & Mouta-Bellum, LLP
OBVIOUSNESS
▪ Graham v. John Deere Co., 383 U.S. 1 (U.S. 1966)
▪ “[if] the difference between the subject matter sought to be patented and the prior art… would have been obvious at the time to a person skilled in the art, then the subject matter cannot be patented.”
▪ Satisfying §103 is legal question with factual underpinnings:
▪ the scope and content of the prior art;
▪ differences between the prior art and the claims at issue; and
▪ the level of ordinary skill in the pertinent art.
▪ And “[s]uch secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., … may have relevancy.”
6© ALGM
OBVIOUSNESS
• What does it take to prove it? Most often (PTAB):
▪ Rationale of teaching or suggestion of all claimed elements
&
▪ Showing that a skilled artisan would have been motivated to combine/modify the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so.
7© ALGM
▪ Unexpected results
▪ Compare to closest prior art?
▪ Compare to closest example within closest prior art?
▪ Showing must be commensurate in scope with the claims
▪ PTAB found that patentee did not sufficiently establish that “the efficacy of a subcutaneous 40 mg biweekly dosing regimen would have been unexpected. Nor [did] Patent Owner compare that dosing regimen to the closest prior art.”
▪ Boehringer Ingelheim Int’l GmbH v. AbbVie Biotechnology Ltd., IPR2016-00408 and IPR2016-00409
8© ALGM
commercial success
long-felt need failure by others
copying teaching away
initial disbelief and subsequent
acclaim by experts
9© ALGM
▪ “Before delving into the specific arguments and evidence of secondary considerations, we note that it is not sufficient that a product or its use merely be within the scope of a claim in order for objective evidence of nonobviousness tied to that product to be given substantial weight. There must also be a causal relationship, termed a “nexus,” between the evidence and the claimed invention. …A nexus is required in order to establish that the evidence relied upon traces its basis to a novel element in the claim, not to something in the prior art. …Objective evidence that results from something that is not “both claimed and novel in the claim,” lacks a nexus to the merits of the invention. … All types of objective evidence of nonobviousness must be shown to have nexus. …The stronger the showing of nexus, the greater the weight accorded the objective evidence of nonobviousness.”
▪ Tandus Flooring, Inc. v. Interface, Inc., IPR2013-00527, Paper 48 (PTAB Feb. 12, 2015)
10© ALGM
▪ Patent Owners having not much success so far with objective evidence of nonobviousness - not showing nexus (linking the objective evidence of obviousness to the merits of the claimed invention).
▪ PTAB was not persuaded by objective evidence of nonobviousnessin a MOT patent, such as the commercial success of Humira® and long-felt need. The PTAB held that AbbVie did not sufficiently establish nexus between the objective evidence and the claimed dosing regimen rather than the (separately patented) humanized D2E7 antibody itself.
11© ALGM
12Source: Finnegan research as of Aug. 23, 2019, on 60 denials. May be more than one ground for denial.
314(a), 1,
1%
325(d), 6,
8%
Reference
not prior
art, 17,
21%
Claim
limitation
not
present,
20, 25%
No
reasonable
motivation
to
modify/co
mbine, 23,
29%
No
reasonable
expectation
of success,
13, 16%
© ALGM
13Source: Finnegan research as of Aug. 23, 2019 on 155 filed antibody petitions. “granted” includes petition granted on at least one claim pre-SAS; grant rate = granted/granted + denied. May be more than one type of claim challenged per petition.
Composition/
formulation, 21,
18%
Compound
24
15%
Product
7
5%Method of making
6
4%
Method of treatment
87
56%
Method of use
2
1%
What types of claims are being challenged?
© ALGM
Institution Rate in AntibodyIPR Petitions by Type of Claim
14
Source: Finnegan research as of Aug. 23, 2019, on 133 institution decisions. Note: some petitions have more than one type of claim challenged.
Rate = granted on at least one claim/granted + denied. Chart does not include settlements, dismissals, adverse judgments prior to institution.
67%
4/6
70%
16/23
40%
12/30
56%
44/78
METHOD OF
MAKING
COMPOUND COMP/FORM METHOD OF
TREATMENT
© ALGM14
RATIONALES FOR FINAL WRITTEN DECISIONS WHERE
ALL INSTITUTED CLAIMS SURVIVED
Source: Finnegan research as of Aug. 23, 2019, on 15 FWDs where all claims survived. May be more than one reason for
finding Petitioner did not show the claims were unpatentable. 15
no reasonable
expectation of
success
5
no reasonable
motivation to
combine/modify
3
claim limitation
not present
5
ref not prior art
6
© ALGM
Source: Finnegan research as of Aug. 23, 2019, on 48 granted IPRs with FWDs. “mixed” means at least one claim
survived and at least one claim found unpatentable.
16
FWDS IN ANTIBODY IPRS BY CLAIM TYPE
22% 18%
38%
56%
18%
0%
22%
64% 63%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Compound Comp/form Method of
treatmentAll claims survived Mixed All claims unpatentable
16© ALGM
17
• Composition/formulation claims have the best chance
of withstanding an IPR challenge initially (lowest
institution rate).
• If IPR instituted, method of treatment claims have
highest rate of all claims surviving, but
composition/formulation claims have the lowest rate of
all claims canceled.
© ALGM
Regents of the Univ. of Cal. v. Broad Inst., Inc., 903 F.3d 1286 (Fed. Cir. 2018)
Board found no reasonable expectation of success in applying the system in eukaryotic cells.
Federal Circuit affirmed: substantial evidence supports lack of RES
• Too many differences between the two systems
• Concerns that it could work, could be degraded, toxic
• UC’s own expert had concluded in 2012 that whether the CRISPR-Cas9 system will work in
eukaryotes “remains to be seen” and “[o]nly attempts to apply the system in eukaryotes will
address these concerns.”
• Inventor had stated that their “2012 paper was a big success, but there was a problem. We weren’t
sure whether CRISPR/Cas9 would work in eukaryotes.” Many frustrations. And success in doing so
would be “a profound discovery.”
18© ALGM
Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359 (Fed. Cir. 2016)
• if the references cited in an allegation of obviousness provide reasons why a skilled
artisan would not have combined them, it negates a "motivation to combine" and not a
"reasonable expectation of success" of ultimately combining the references
• the Board should have identified a reasonable expectation of making the claimed
invention, not of combining the references for the purposes found in the prior art
• Federal Circuit "sit[s] to review judgments, not opinions," citing Stratoflex, Inc. v. Aeroquip
Corp., 713 F.2d 1530, 1540 (Fed. Cir. 1983).
• Affirmed
19© ALGM
Region encompassed
by Genetics’ Deletions
Retained by Novartis
Region encompassed
by Novartis’ Deletions
20© ALGM
▪ lack of any reason to create a truncated protein that incorporated the 1649-1689 region
▪ Any motivation would have been in the opposite direction – to create a shorter protein and eliminate more amino acids, not to create a longer protein
▪ mere existence of a cleavage site was not sufficient to provide the requisite reason to cut the protein at that point to make the claimed truncated protein
Genetics Institute, LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291 (Fed. Cir. 2011)
21© ALGM
• Novartis’ preservation of the a3 region produces a protein with unexpectedly improved activity
• "[E]very property of a claimed compound need not be fully recognized as of the filing date of a patent application to be relevant to nonobviousness." Slip Op. at 29. In other words, "evidence of unexpected results may be used to rebut a case of prima facie obviousness even if that evidence was obtained after the patent's filing or issue date."
22© ALGM
▪ 1. An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5-8.▪ Prior art taught a mouse TA.1 mMab-DM1 conjugate.
▪ POSITA would not have been motivated to replace TA.1 with Herceptin evidence at the time suggested such construct to have unacceptable levels of ADCC.
▪ Immunogen also presented evidence of difficulty and unpredictability when preparing “any antibody-toxin immunoconjugate,” lack of a reasonable expectation of success in the claimed invention.
▪ In addition, Immunogen’s objective evidence of nonobviousness related to the commercial success of T-DM1/Kadcyla® supported the patentability of other claims.
Phigenix, Inc. v. Immunogen, Inc., IPR2014-00676, Paper 39 (P.T.A.B. Oct. 27, 2015)
23© ALGM
▪ “In view of the specific components recited in claim 8, i.e., a specific antibody, linker, and toxin, which are the same as those in T-DM1/Kadcyla®, we are persuaded that Patent Owner establishes a sufficient nexus in relation to the cited objective evidence of nonobviousness.”
▪ “The specification of the ’856 patent discloses, and claim 8 recites, the very components that led to the unexpected results, praise and commercial success….Patent Owner sufficiently establishes that it is the exact combination of those components recited in claim 8, rather than different components previously combined in the prior art, that provided the unexpected results at issue, and led to praise and commercial success.”
24© ALGM
• Antibody, linker, drug not known
• POSA not motivated to modify known components to make the ADC
• POSA would not have had a reasonable expectation of success
• Claimed ADC shows unexpected results
25© ALGM
▪ Unpredictability, objective evidence: commensurate in scope?
▪ PTAB: Original claims unpatentable but granted motion to amend proposing substitute claims.
▪ Objective evidence of unexpected results was not commensurate in scope with the instituted original claims but was sufficient to overcome prima facie case of obviousness for two proposed substitute claims.
▪ Valeo North America, Inc. v. Schaeffler Tech. AG & Co. KG, IPR2016-00502, Paper 37 (P.T.A.B. June 20, 2017)
▪ Commercial success and unexpected results were commensurate in scope in narrow claim to Kadcyla (Phigenix v. Immunogen)
26© ALGM
© ALGM
In re Kubin (561 F. 3d 1351) (Fed. Cir. 2009)
An isolated nucleic acid molecule comprising a polynucleotide
encoding a polypeptide at least 80% identical to amino acids
22-221 of SEQ ID NO:2, wherein the polypeptide binds CD48.
The prior art disclosed:
1. The protein called “NAIL” encoded by the nucleic acid;
2. Antibodies specific to the protein; and
3. Cloning techniques for obtaining the polynucleotide.
27
• Kubin (con’t)• Board:
• “one of ordinary skill in the art would have recognized the value of isolating NAIL cDNA, and would have been motivated to apply conventional methodologies, such as those disclosed in Sambrook and utilized in Valiante, to do so.”
• “appellants’ claim was “‘the product not of innovation but of ordinary skill and common sense,’ leading us to conclude NAIL cDNA is not patentable as it would have been obvious to isolate it.”
28© ALGM
FC: Affirmed.
A very narrow repudiation of 1995 Deuel opinion in favor of its 1988 O’Farrell opinion and the Supreme Court’s KSR opinion.
“Supreme Court repudiated as “error” the Deuel restriction on the ability of a skilled artisan to combine elements within the scope of the prior art:
The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try.’ When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”
29© ALGM
• Boehringer Ingelheim Int’l GmbH v. AbbVie Biotechnology Ltd., IPR2016-00408, HUMIRA®
▪ just because other doses might have had better efficacy than the claimed dose does not represent a teaching away
▪ “[a] reference teaches away from the claimed invention if it criticizes, discredits, or would have discouraged a person of ordinary skill in the art from ‘following the path set out in the reference,’ or if a person of ordinary skill ‘would [have been] led in a direction divergent from the path that was taken by the applicant.’ In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994); see In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). The mere disclosure of alternative designs, however, does not teach away. In re Mouttet, 686 F.3d 1322, 1333–34 (Fed. Cir. 2012).” IPR2016-00408
30© ALGM
▪ Proceeding contrary to the accepted wisdom in the art represents “strong evidence of
unobviousness”
▪ “Trade-offs often concern what is feasible, not what is, on balance, desirable. Motivation to
combine requires the latter.”
▪ Winner Int’l Royalty Corp. v. Ching-Rong Wang, 202 F.3d 1340 (Fed. Cir. 2000).
▪ Merely because a reference does not describe a particular feature does not automatically
mean it teaches away from the claimed invention.
▪ In re Inland Steel Co., 265 F.3d 1354, 1361 (Fed. Cir. 2001).
▪ Mere disclosure of alternative designs does not teach away.
▪ In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004).
31© ALGM
E. I. du Pont de Nemours & Co. v. Synvina C.V. (Fed. Cir. 2018)
court recognized “several ways by which the patentee may rebut that presumption.”
▪ If the claimed process parameter “produce[s] a new and unexpected result which is different in kind and not merely in degree from the results of the prior art.” (based on Aller)
▪ If the prior art taught away from the claimed range
▪ If the parameter was not recognized as “result-effective.” (based on In re Applied Materials, Inc., 692 F.3d 1289 (Fed. Cir. 2012))
▪ If the prior art discloses “very broad ranges” which “may not invite routine optimization.” (based on Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291 (Fed. Cir. 2011))
32© ALGM
• Merck v Pfizer IPR2017-02131 Prevnar 13
• “In cases involving overlapping ranges, we and our predecessor court have held ---it establishes a prima facie care of obviousness.” In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003)
• Evidence showed that optimization of polysaccharide conjugate size was routine to the POSA: conjugate size known to be a result effective variable associated with improved products
• POSA would have found the claimed range desirable and would have had a reasonable expectation of achieving a product within that range
• “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955)
33© ALGM
1. A method of treating rheumatoid arthritis in a human patient who experiences
an inadequate response to a TNFα-inhibitor, comprising administering to the
patient an antibody that binds to CD20, wherein the antibody is administered as
two intravenous doses of 1000 mg.
Petitioner did not establish that dose-sizing option (fixed vs. dosing based on
surface area), total dose number of infusions, amount of each infusion, were
result-effective variables such that a person of skill in the art would have reason
to optimize (In Re Antonie, 559 F.2d 618, 620 (CCPA 1977).
Celltrion v. Genentech, Inc., IPR2016-01667
34© ALGM
Unpredictability can be important: show that invention was not predictable.Show no reasonable expectation of success.
Show there was not a “finite number of identified, predictable solutions.”
Show unexpected results ??
Other objective indicia of nonobviousnes??
Will that effect scope of enablement?
Show teaching away, particularly in so-called predictable results.
Showing lack of predictability or expectation of success may require
submitting data and/or declarations earlier in prosecution; evidence to
destroy, not rebut, the prima facie case.
35© ALGM
THANK YOU
Carla Mouta-Bellum, Ph.D., J.D.Arrigo, Lee, Guttman & Mouta-Bellum, LLP2200 Pennsylvania Ave. NW4th Floor EastWashington, D.C. 20037 e-mail: [email protected]: +1 (202) 316-3025Fax: + 1 (202) 318-8359Web: www.arrigo.us
36© ALGM
These materials have been prepared solely for educational and entertainment purposes to contribute to the understanding of U.S. and European intellectual property law. These materials reflect only the personal views of the authors and are not individualized legal advice. It is understood that each case is fact specific, and that the appropriate solution in any case will vary. Therefore, these materials may or may not be relevant to any particular situation. Thus, the authors, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP (including Finnegan Europe LLP, and Fei Han Foreign Legal Affairs Law Firm) cannot be bound either philosophically or as representatives of their various present and future clients to the comments expressed in these materials. The presentation of these materials does not establish any form of attorney-client relationship with these authors. While every attempt was made to ensure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed.
37© ALGM
mathys-squire.com
Obviousness of Biologics Inventions in Europe
Hazel Ford
Mathys & Squire LLP
mathys-squire.com
Obviousness/Inventive Step at the EPO• Problem and solution approach
▪ Based on a comparison with the “closest prior art”
▪ What problem is solved by the claimed invention compared to the closest prior art?
▪ Is the claimed solution to that problem obvious?
• Not simply whether it would have been obvious to produce the claimed product
▪ How does the claimed product differ from other products in the prior art?
▪ What is the effect of the structural differences?
▪ Do the differences lead to any unexpected advantages?
• If there is an unexpected advantage, problem may be based on those advantages
• If there is no unexpected advantage compared to closest prior art, problem may be to provide an alternative
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No Advantage – Providing an Alternative
• Was it routine to obtain and screen for products of this type?
• Is there any technical reason why this product would not have been found by routine/trial and error methods?
• EPO makes a number of assumptions about antibodies
▪ Antibody structure/function relationships well known
▪ Methods for producing, modifying, humanizing etc., all considered routine
▪ Routine antibody production methods allow production of large numbers of antibodies against a given target
• EPO often considers that an antibody having essentially the same binding properties as a prior art antibody would have been found (…eventually) by trial and error
▪ Even if the antibodies are structurally different from each other
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“The particular … antibodies which are the subject-matter of claim 1 … do not provide the art with any unexpected property or functional advantage in the sensitivity or the specificity, for instance, and are not functionally different from those described in document (2). The case law in this field acknowledges inventive step if and when there is evidence that a claimed monoclonal antibody prepared by routine methods shows unexpected properties (cf decision T 645/02 of 16 July 2003). If, however, there are no unexpected effects achieved with a further monoclonal antibody compared with a monoclonal antibody with essentially the same properties as desired the case law denies inventive step (cf decision T 512/94 of 23 June 1998).”
T 735/00Anti-CRP antibodies IATRON LABORATORIES, INC.
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“the skilled person starting from the closest prior art, represented by document D1, and faced the technical problem of providing additional monoclonal anti-CXCR-4 antibodies useful for treating diseases in which pathogenesis is mediated by CXCR4 and SDF-I … and having knowledge of how to prepare such antibodies … would have been motivated to apply those known techniques to arrive at antibodies that solve the technical problem in an obvious manner. All such antibodies would therefore have been obvious to the skilled person, the claimed antibody being one of many potential anti-CXCR-4 antibodies, each of which representing an obvious solution to the technical problem.”
EP 2 297 206Preliminary opinion of the Board of Appeal
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Unexpected Properties• If the claimed product provides an unexpected advantage, then the problem might be
how to obtain that advantage
▪ New or improved biological activity
▪ Significant improvement in affinity
▪ Cross-reactivity
▪ Low immunogenicity
▪ Pharmacokinetic properties
▪ Expression level
▪ Stability in solution
▪ Reduced toxicity in vivo
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Are Some Advantages Better Than Others?
• “The skilled person with a knowledge of [other antibodies against the same target] and intent on producing further antibodies would produce a mixture of antibodies with different properties and select them according to their functionality or affinity, depending upon the intended application”
• “Moreover, in the present case, the specific structure of the variable heavy and light chain amino acid sequences of [the antibody] does not impart an additional property to the antibody which differs from the property screened for and which could be regarded as surprising”
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mathys-squire.com
Plausibility• “Plausibility” is a requirement that can be applied in relation to sufficiency/enablement
or in relation to inventive step
• Enablement/sufficiency of disclosure
▪ Can the invention be carried out across the scope of the claims?
▪ E.g., for a treatment claim:
• Is it plausible that the treatment will work?
• Is it plausible that substantially all agents in the claims will be effective at treating substantially all diseases in the claims?
• Inventive Step
▪ Has the problem been solved?
▪ E.g., where inventive step is based on an unexpected advantage or property compared to the closest prior art:
• Is it plausible that the advantage/property will actually be achieved?
• Is it plausible that it will be achieved across the scope of the claims?
45
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Had the Problem Actually Been Solved…?• If inventive step is based on an unexpected advantage or effect, it must be technically
plausible from the information in the application as filed that your invention does actually achieve that effect
▪ was the advantage demonstrated in the application as filed?
▪ did the application include enough information to at least suggest that the effect would be achieved?
▪ did the application include a plausible technical reason why the effect would be achieved?
• Post-filing data can only be taken into account to show an advantage if that advantage was at least plausible based on the information in the application as filed
▪ “…even if supplementary post-published evidence may in the proper circumstances be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve.” - T 1329/04 (Factor-9/John Hopkins)
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mathys-squire.com
• Appellant alleged that claimed antibodies have the unexpected ability to induce immunotolerant T-cells
▪ “The application does not explicitly disclose that the claimed antibodies induce immunotolerant T-cells.”
▪ “…the examples of the application do not point to the induction of immunotolerance”
▪ “…the common general knowledge would not have prompted the skilled person to infer from the suggested use of the antibodies claimed for transplantation therapy that this is based, at least in part, on the antibodies' ability to induce immunotolerance”
▪ “…the board concludes that it is not derivable from the application that the claimed antibodies induce immunotolerant T-cells and this effect cannot accordingly be relied on for the formulation of the technical problem”
T 2637/11Anti-TIRC7 monoclonal antibody
CELLACT
47
mathys-squire.com
• Examples: synthesis of 580 compounds within a general formula, description of assays for testing activity
▪ “Compounds described in the following examples have been tested in one or more of these assays and have shown to have activity”
• In opposition/appeal, single claim filed to dasatinib, supported by post-filing data
▪ “…no information is provided as to which of the structurally rather different compounds had been tested and in which assay, in particular whether any of the tests included dasatinib”
▪ “If…the invention…relies on a technical effect, which is neither self-evident nor predictable or based on a conclusive theoretical concept, at least some technical evidence is required to show that a technical problem has indeed been solved.”
▪ “…the issue is not the absence of any in vivo data or clinical data, but rather the absence of any verifiable data with regard to the asserted technical effect.”
T 488/16Dasatinib
BRISTOL-MYERS SQUIBB
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mathys-squire.com
…Across the Scope of the Claims?• If an inventive step is based on an unexpected advantage, then that advantage must be
obtained across the scope of the claims
▪ “When defining the objective technical problem an effect cannot be retained if it is not credible that the promised result is attainable throughout the entire range covered by a claim … If the inventive step of a claimed invention is based on a given technical effect, the latter should, in principle, be achievable over the whole area claimed” (Case Law of the Boards of Appeal I.D.4.3)
• Which characteristics of your product are responsible for the advantage that you rely on?
• Which variants would the skilled person expect to retain the advantage?
▪ variations in particular parts of the molecule
▪ particular types of variation (e.g. conservative substitutions)
▪ do you provide a technical explanation for the effect?
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mathys-squire.com
• “An antibody which binds to the epitope bound by the 8B8 antibody obtainable from the hybridoma cell line ATCC no. HB-12070”
▪ Antibody binds ErbB3, and shown to increase binding affinity of ErbB3 to heregulin
▪ Unexpected that binding an antibody to ErbB3 would increase its binding to heregulin, rather than inhibiting/interfering with binding
▪ Plausible that the surprising effect of this antibody would be shared by other antibodies binding the same epitope
T 2045/09Anti-ErbB3 antibody
GENENTECH
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mathys-squire.com
• Alleged technical contribution = that increased fucosylation(at least 99%) of an antibody would reduce ADCC to background, even at high antibody concentrations
• “The patent never says this in words”
• Court found that data in the patent
▪ make it plausible that the tested antibody reduces ADCC
▪ make it plausible that no ADCC was found at the concentration tested
▪ do not make plausible that the same effect would be seen at higher concentrations or with other antibodies
• Does the patent plausibly demonstrate a technical contribution to the art?
▪ Is it disclosed in the patent?
▪ Is it plausible?
▪ Is it true?
▪ Is it a technical advance?
▪ Does it support claims of this breadth?
Takeda v Roche[2019] EWHC 1911
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mathys-squire.com
Conclusions• Particularly for antibodies, structural non-obviousness alone is unlikely to be enough
▪ may need something surprising or unexpected compared to the closest prior art
• Is it plausible that the advantage actually exists?
▪ based on the information in the application and the common general knowledge
• if you don’t have supporting data at filing, try to include technical explanation of why it is expected to show an improvement
▪ across the whole scope of your claims
• consider whether including more Examples might help
• if you don’t have data for more Examples, try to include technical explanation that supports why the improvement would be seen across the claim scope
▪ be prepared – include a variety of narrower fall-back positions in your application in case the EPO considers the claims are broader than the invention
• bear in mind EPO’s strict test on basis for amendments – if you don’t include in your application at filing, you might not be able to make those amendments in prosecution
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Please contact Hazel Ford for further information at:
Mathys & Squire LLPThe Shard32 London Bridge StreetLondon SE1 9SG
T +44 (0)20 7830 0000F +44 (0)20 7830 0001
www.mathys-squire.com
Contact
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Definition for Inventiveness
Article 22, paragraph 3 of the Chinese Patent Law:
Inventiveness means that, as compared with the prior art, the invention has prominent substantive features (i.e., non-obviousness) and represents a notable progress (beneficial technical effect).
For biologics inventions, “beneficial technical effect” is widely interpreted at “advantageous effect”, and even “unexpected effect”
Approach for Determining
Inventiveness The “Three-Step” Approach Under the Guidelines For Determining the Inventiveness of an Invention
• Identifying the closest prior art;
• Determining the distinguishing technical features and the technical problem actually solved by the invention; and
• Determining whether the invention is non-obvious to a person skilled in the art, i.e., whether the prior art provides motivation to apply the distinguishing technical features to the closest prior art to solve the technical problem actually solved by the invention.
Approach for Determining
Inventiveness
• Technical effect is a particularly important consideration for biologics inventions
• Difficult to establish inventiveness by structural non-obviousness alone
• Post-filing data is practically not acceptable to establish inventiveness
Inventiveness of Antibodies
How can a monoclonal antibody claim be defined
(☺) By the producing hybridoma(☺) By structural features, with or without functional features() By functional features only: epitope, competitive binding, Kd…-will be rejected for lacking support
※ For definition by hybridoma, the relevant hybridoma must be deposited prior to filing.
※ For definition by structure, at least all of the six CDRs have to be specified.
Exemplary Structural
Definitions
• Sequences of 6 CDRs (☺)
• H and L chain variable region sequences (☺)
• H and L chain sequences (☺)
• 6 CDRs from a given H-L chain pair (☺)
• H chain CDR3 only ()
• H or L chain only ()
• CDRs from a CDR pool ()
Inventiveness of Antibodies
Inventiveness of monoclonal antibody (Part II, Chapter 10, Section 9.4.2.1 of the Guidelines)
If an antigen is known and it is clearly known that the antigen has immunogenicity, the invention of a monoclonal antibody of the antigen does not involve an inventive step. However, if the invention is further defined by other features, and hence has unexpected technical effects, the invention of that monoclonal antibody involves an inventive step.
Inventiveness of Antibodies
Inventiveness of antibodies defined by 6 CDRs
The structural differences in the CDRs are not enough to establish the inventiveness of an antibody defined by 6 CDRs.
An antibody defined by 6CDRs does not involve an inventive step if no unexpected technical effect of the antibody is disclosed in the description as filed.
Inventiveness of Antibodies
Unexpected technical effects (UTE)
Structural differences in the CDRs are not enough to establish the inventiveness of an antibody defined by 6 CDRs.
An antibody defined by 6CDRs does not involve an inventive step if no unexpected technical effect of the antibody is disclosed in the description as filed.
Inventiveness of Biologics
Inventions Gene
If the amino acid sequence of a protein is known, an invention of a gene encoding the protein does not involve an inventive step. However, if the gene has a particular base sequence and has unexpected technical effects compared with other genes having a different base sequence encoding said protein, the invention of said gene involves an inventive step.
generally presumed obvious
until UTE proven:
• A natural variant coding gene of a known protein
• Codon-optimized coding sequence of a known protein
UTE is key. How to assess it?
Guidelines says that UTE means, compared to prior art, the invention provides
• a new, unpredictable technical effect (kind)
• A known technical effect at a level exceeding PHOSITA’s expectation (amount)
How to choose the “prior art” for comparison remains opaque
• the closest prior art as used in the obviousness assessment?
• the best-performing prior art in evidence?
• Conveniently chosen from the art in general?
Case 1: PRB Decision No.
109361• Claim: an anti-EGFR mAb (m175) defined by 6
CDRs
• Spec: contains data comparing m175 and m806
• D1: anti-EGFR mAb (m806) for the same epitope, each CDR differing from that of m175 by 1 amino acid
Reasoning of Final Rejection
• Alternative antibodies for a known epitopeare presumed obvious
• PHOSITA could easily make m175 from m806 by conventional substitution
• mAb1 does not produce UTE, as Spec shows m175 has lower antitumor effect than m806 in a cell type
PRB reverses, holding
• Substitution of CDRs is no routine practice as changing CDRs unpredictably affects activity
• m175 is non-obvious over m806 by virtue of distinct CDRs
• m175 outperforms m806 in at least oneaspect (spec shows m175 had better effect in another cell type), which could not have been unpredicted from their structural differences. UTE is thus recognized.
Case 2: PRB Decision No.
113596• Claim: anti-EpCAM antibody defined by
epitope sequence & hybridoma deposit No.
• Spec: presents data showing tumor-inhibiting effect of the antibody.
• D1: hybridoma antibodies raised with the same antigen peptide. No disclosure of tumor inhibition .
Reasoning of Final Rejection
• The spec does not show better specificity or affinity of the claimed antibody over D1’s.
• Many anti-EpCAM antibodies capable of treating tumors are known in the art, thus the tumor-inhibiting effect is not a UTE.
PRB reverses, holding
• Although hybridoma technology is well-established, obtaining a particular mAb is contingent and random.
• Whether a particular mAb has therapeutic effect is unpredictable. The spec has data to prove the effect while D1 has not. PHOSITA cannot predict the claimed antibody has such an effect from D1. UTE recognized.
Case 3: PRB Decision No.
87391• Claim: a humanized Ab defined by H chain and
L chain variable region sequences
• D1: a murine Ab having the same CDRs (the parent Ab)
• Spec shows the Kd of the claimed Ab (3.17nM) is slightly lower than the parent Ab (4.19 nM), whereas another humanized Ab has higher Kd.
Applicant’s arguments
• The impact that humanization has on the binding affinity is unpredictable. PHOSITA could not foresee the decreased Kd (hence improved affinity) of the claimed antibody
• Submitted supplemental data to show the claimed Ab has superior effect to parent Ab
PRB affirms, holding
• Humanization is common knowledge. Sequence of a particular humanized Abcannot make it patentably distinct from other potential humanized antibodies.
• Fluctuation of affinity among humanized Abs is within PHOSITA’s expectation. The slightly decreased Kd does not amount to UTE.
• Supplemental data rejected
Summary
• UTE is more relied upon for showing inventiveness inbiotech than other areas
• UTE must be explicitly disclosed & supported by datain as-filed application
• Abs having new CDRs fare better than those having not. PRB takes a more liberal approach in assessing UTE of Abs with new CDRs than it does in other areas (e.g. does not require head-to-head comp with prior art).
Recent trend
• UTE requirement becomes less stringent with pharmaceutical antibodies (e.g. PD-1/PD-L1 antibodies)
Thank you!