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 .
DETAILED ACTION
The Amendment filed 3/24/2026 in response to Office Action of 12/3/2025, is acknowledged and has been entered. Claims 1-19 and 43-68 are now pending. Claims 1 and 2 are amended. Claims 1-19 and 43-68 are currently being examined.
Maintained Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 and 43-68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION Rejection.
The claims are drawn to an antibody or antigen-binding antibody fragment thereof that specifically binds to HER2 protein, said antibody or antigen-binding antibody fragment thereof comprising a heavy chain variable region including three complementarity determining regions, having amino acid sequences H1, H2 and H3, wherein: the H1 sequence is (SEQ ID NO: 1) GFX1IKDTYIH; the H2 sequence is (SEQ ID NO: 2) X2IX3PTX4X5YX6X7YADSVKG; and the H3 sequence is (SEQ ID NO: 3) WGGDGFYX8MDY;
wherein X1 is N or W, X2 is R or K, X3 is Y or K or D, X4 is N or A, X5 is G or K, X6 is T or D, X7 is R or E and X8 is A or E; and
a light chain variable region including three complementarity determining regions having amino acid sequences L1, L2, and L3, wherein:
the L1 sequence is (SEQ ID NO: 4) RASQDVNTX9VA; the L2 sequence is (SEQ ID NO: 5) SASFLYS; and the L3 sequence is (SEQ ID NO: 6) QQX10YTTPPT,
wherein X9 is A or D and X10 is H or D or E;
and provided that X1 to X10 are not N, R, Y, N G, T R, A, A, and H respectively at the same time; and wherein a binding affinity of the antibody or the antigen-binding fragment thereof at a pH of 5.0 o 6.8 is greater than the binding affinity of the antibody or antigen-binding fragment thereof at a pH of 7.0 to 7.6, and
the antibody or antigen-binding antibody fragment has up to one single point mutation in one of the H1, H2, and H3 sequences of the heavy chain variable region and up to two-point mutations in L1 and L3 sequences of the light chain variable region, each in comparison with the parent antibody, or antigen-binding antibody fragment in which X1-X10 are N, R, Y, N G, T, R, A, A, and H, respectively.
Thus, the claims are drawn to an antibody or antigen-binding fragment with a vast number of antibody variants and various combinations of CDRs or variable regions.
The instant specification discloses exemplary isolated anti-HER2 polypeptides in paragraphs [0142] and [0143] of the published specification. However, the instant specification only provides examples of 9 clones in Table 2 testing the binding activities of the conditionally active Anti-HER2 antibodies. Thus, the instant specification does not provide adequate support for all the possible variants of the anti-HER2 antibodies that function to bind to HER2 at a pH of 5.0 to 6.8 greater than pH of 7.0 to 7.6.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
With regards to anti-HER2 antibodies, Sulea, et al. (Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment. MAbs. 2020;12(1):1682866) teaches that modifying antibody-antigen affinity by mutagenesis of CDR to an optimal range where binding to low-density antigen on normal cells is reduced while a reasonable level of binding to the high-density antigen present on tumor cells is retained. Sulea proposes a strategy that exploits the higher acidity of the tumor relative to normal tissues pH. Sulea notes that due to poor vasvular perfusion, regional hypoxia and fermentative glycolysis, the extracellular pH in most solid tumors is 6.0-6.8 range and noncancerous cells maintain the extracellular pH at a physiological level 7.3 – 7.4. Sulea teaches that predicting pH-dependent antigen-binding CDRs of antibodies is limited. [pg 1, introduction] Sulea also teaches that in vitro functional efficacy on growth inhibition after modifying CDR regions to bind to the antigen at a lower pH, it is unknown whether this would translate in vivo. [pg 10]
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies or antigen binding proteins that function as listed aboe, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. T
Given the lack of representative examples to support the full scope of the claimed antibodies that bind to HER2 at a lower pH, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the antibodies that function as claimed, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Response to Arguments
Applicants argue the following: The claimed genus is structurally defined and limited: Applicants argue that that the claims recite specific structural limitations by defining the amino acid sequences of the six CDRs that form the antigen binding site. Applicant argues that preparation, characterization, and optimization of antibodies is a routine and reasonably predictable undertaking for a person of ordinary skill in the art when there is a clear structural framework (defined CDRs). Applicant argues that Sulea et al is misplaced. Applicant argues that the specification provides representative examples and clear structure-function correlation.
Applicant’s arguments have been considered but are not persuasive. As noted above, the claims the claims are drawn to an antibody or antigen-binding fragment with a vast number of antibody variants and various combinations of CDRs or variable regions. The CDR regions are not defined as the Applicant states:
H1 sequence: (SEQ ID NO: 1) GFX1IKDTYIH;
H2 sequence: (SEQ ID NO: 2) X2IX3PTX4X5YX6X7YADSVKG;
H3 sequence: (SEQ ID NO: 3) WGGDGFYX8MDY;
wherein X1 is N or W, X2 is R or K, X3 is Y or K or D, X4 is N or A, X5 is G or K, X6 is T or D, X7 is R or E and X8 is A or E; and
L1 sequence (SEQ ID NO: 4) RASQDVNTX9VA
L2 sequence (SEQ ID NO: 5) SASFLYS;
L3 sequence is (SEQ ID NO: 6) QQX10YTTPPT,
wherein X9 is A or D and X10 is H or D or E;
and provided that X1 to X10 are not N, R, Y, N G, T R, A, A, and H respectively.
Furthermore, the claim also recite up to one single point mutation in H1, H2, and H3 and up to two point mutations in L1 and L3.
The CDR sequences are not well defined. For example, H1 itself can have up to 382 variants (including up to 1 additional mutation), H2 can have up to 209 variants (not including the one point mutation), H3 can have up to 418 mutations (including the 1 additional mutation). Thus, contrary to Applicant’s arguments, they are not defined. Sulea, et al. teaches that modifying antibody-antigen affinity by mutagenesis of CDR to an optimal range where binding to low-density antigen on normal cells is reduced while a reasonable level of binding to the high-density antigen present on tumor cells is retained. Sulea teaches that predicting pH-dependent antigen-binding CDRs of antibodies is limited. Sulea also teaches that in vitro functional efficacy on growth inhibition after modifying CDR regions to bind to the antigen at a lower pH, it is unknown whether this would translate in vivo. [pg 10] The instant specification only provides examples of 9 clones in Table 2 testing the binding activities of the conditionally active Anti-HER2 antibodies. The instant specification also does not provide examples or demonstrate which mutations can be made to still retain activity. Thus, the instant specification does not provide adequate support for all the possible variants of the anti-HER2 antibodies that function to bind to HER2 at a pH of 5.0 to 6.8 greater than pH of 7.0 to 7.6.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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