DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 4, 6-15, 21-24, and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1 and 3 are under consideration in this office action.
Withdrawn Rejections
The rejection of claim 3 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of applicant’s amendment.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180312588A1, published November 1, 2018 (“Wiltzius”; see instant PTO-892.
The claims are directed to a polypeptide comprising a single chain variable fragment (scFv) that targets CD19. The scFv of SEQ ID NO: 1 is comprised of a variable light chain region (SEQ ID NO: 50), a spacer, and a variable heavy chain region (SEQ ID NO: 54).
Wiltzius teaches a humanized anti-CD19 scFv [0079] of SEQ ID NO: 26. This scFv has a light chain variable region comprised of three complementarity determining regions (CDRs) of SEQ ID NOs: 27-29 [0017] and a heavy chain variable region comprised of CDRs of SEQ ID NOs: 32-34 [0019]. These six CDRs in Wiltzius SEQ ID NO: 26 are identical to those found in instant SEQ ID NO: 1. See alignment below (boxes indicating six CDRs), where Qy is instant SEQ ID NO: 1 and Db is SEQ ID NO: 26 of Wiltzius.
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Wiltzius also teaches the spacer of SEQ ID NO: 7, which is identical to the spacer of instant SEQ ID NO: 1 (GSTSGSGKPGSGEGSTKG starting at position 110). Thus, Wiltzius teaches a scFv comprised of the same anti-CD19 antigen binding domain and the same spacer from instant claim 1 and 3.
Wiltzius teaches that the variability in antibody sequence is concentrated in the CDRs, while the more highly conserved regions in the variable domain are called framework regions (FR); the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen [0116]. The differences in sequence identity between the scFv of Wiltzius and the scFv claimed are only in the framework regions.
Given that Wiltzius teaches the antigen binding domain of the scFv, it would have been obvious to one of ordinary skill in the art that the scFv of Wiltzius is the same as that claimed. The ordinary artisan would be able to modify the framework regions of the scFv to arrive at the claimed polypeptide comprising SEQ ID NO: 1 using methods already known in the art. Wiltzius teaches the process of antibody humanization, where the non-human antibody frameworks are replaced with those from human [0248]. For example, GenScript® provides a method for humanizing antibodies; the method follows combining CDR-grafting, structure-based back mutation method, and fast Screening for expression level, biophysical properties, and affinity technology (FASEBA), which generates a humanized antibody, e.g., scFv with affinity and optimized properties [0250]. Thus, methods for humanizing murine antibodies and optimizing these antibodies were well known in the art at the time the application was filed. See MPEP 2143.02.II: The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful. The ordinary artisan would recognize the modification of framework regions is a part of routine optimization and would be able to carry out such a substitution via methods known in the art. Without evidence of unexpected results or a teaching away, the claimed polypeptide is obvious over the teachings of Wiltzius.
Response to Arguments
Applicant's arguments filed July 29, 2026 have been fully considered. Applicant asserts that framework modifications are not developed through mere routine optimization with predictable outcome (pg 9). Further, the cited reference Wiltzius and the present specification show that specific framework sequences must be selected and screened to identify the claimed scFv sequences; Wiltzius fails to provide sufficient guidance to one of skill in the art to arrive at the specific framework sequences of SEQ ID NO:1 or SEQ ID NOs:50 and 54 (pg 11). These arguments are not persuasive because Wiltzius teaches an anti-CD19 antibody comprising the same CDRs and numerous examples with variations in the framework regions. Methods for the humanization of antibodies, which includes methods for screening such antibodies by functional characteristics, are also taught by Wiltzius and were routine within the art at the time the application was filed. Wiltzius demonstrates that the ordinary artisan was aware of the criteria that determine a successful scFv and that framework amino acid sequence modification could alter some properties of a scFv, including aggregation and affinity for the target.
As stated in the rejection above, Wiltzius teaches the process of antibody humanization, where the non-human antibody frameworks are replaced with those from human [0248]. For example, GenScript® provides a method for humanizing antibodies; the method follows combining CDR-grafting, structure-based back mutation method, and fast Screening for expression level, biophysical properties, and affinity technology (FASEBA), which generates a humanized antibody, e.g., scFv with affinity and optimized properties [0250]. Thus, methods for humanizing murine antibodies and optimizing these antibodies were well known in the art at the time the application was filed.
When other methods similar to a claimed method, have been successful, the court has determined there would have been a reasonable expectation of success. For example, in Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003), a reasonable expectation of success was found for a method of producing a particular protein when several other proteins had been produced in a similar way. Thus, the decision to select the specific framework amino acid sequences is a part of routine optimization and could be determined by methods well described in the art. In the absence of unexpected results, such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. The implication that one of ordinary skill in the art would not have conceived the framework amino acid claimed is not supported by the state of the art at the time the application was filed.
Overall, it is the examiner’s position that the product of Wiltzius clearly reads on the product claimed. According to the specification, applicant described the development of two CD-19 targeted scFvs by a method including protein engineering and combinatorial library screening (pg 1). Even if the framework amino acid sequences were identified in a potentially new screening method, the patentability of a product does not depend on its method of determination. If the product in the product claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Implementation of a novel method for identifying framework modification in a composition and method is not sufficient when considering a case of nonobviousness over routine optimization.
When making a case of unexpected results to demonstrate nonobviousness, here a change in KD or aggregation, one must consider all the evidence and determine if the evidence of unexpected results outweigh the evidence of obviousness. See MPEP 716.02(d): Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." Looking at Figure 1 of the specification, it is apparent that the humanized scFv of SEQ ID NO: 1 (circles) exhibits less affinity for CD19 than the parental mouse scFv (squares). Applicant is encouraged to submit evidence of unexpected results; any evidence that the claimed frameworks are unexpectedly superior in degree or kind relative to those humanized scFvs in the art will be considered.
Absolute predictability is not a necessary prerequisite for a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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