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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2021/063847, filed 12/16/2021; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/262310, filed 10/8/2021.
Status of Claims
Claims 1-22 are pending and are being examined on the merits.
Claim Rejections - 35 USC § 112(a)
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 and 3-22 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 claims contain 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.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through
sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation
within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would
recognize from the specification the scope of what is being claimed.
Instant claim 1 recites anti-EpCAM polypeptides comprising an immunoglobulin heavy chain variable region comprising CDRs 1-3, whereby CDR-H1 comprises a sequence having at least 90% sequence identity to any of SEQ ID NOs: 1-13, CDR-H2 comprises a sequence having at least 90% sequence identity to any of SEQ ID NOs: 14-26, and CDR-H3 comprises a sequence having at least 90% identity to any of SEQ ID NOs: 27-39; such that any of the CDRs of groups H1-H3 can be mixed and matched to result in an EpCAM binding polypeptide. The “at least 90%” sequence identity component of the CDRs 1-3 are individually iterated in claims 4-6; as well as applying to the nucleic acid encoding the polypeptide of claim 16. Thus, applicants are claiming a genus of anti-EpCAM binding polypeptides with variant CDR sequences and with variant combinations of CDRs.
Regarding the claims to H-CDRs having at least 90% sequence identity to any of the 39 H-CDR sequences. The H3-CDR of instant SEQ ID NO: 27 is 21 amino acids in length; thus the claim encompasses polypeptides having up to 2 amino acid residue differences, whereby the alternative residues may occur at any positions within the 21 amino acid long H3-CDR. There are 20 alternative amino acids that may be substituted at up to 2 residues, in any combination, at any location in the H3-CDR. When any of 20 alternative amino acid substitutions may be made at any single residue, across 21 residues, there are ~420 potential alternative polypeptides. When allowing for two such substitutions the number is doubled; and when contemplating the total number of alternative sequences encompassed across 13 different H3-CDRs, the number of possibilities is further magnified. Thus, the claims are interpreted to encompass a significant number of variant peptides, comprising a sub-genus of any one of the H3-CDR domains of instant SEQ ID NOs: 27-39, with no limitation as to which residues may be substituted, or with which amino acids, and wherein the substitutions may occur anywhere within any of the H3-CDRs. The claims encompass a sub-genus of variant embodiments which comprise unidentified variant CDR sequences; thus, under the broadest reasonable interpretation, claim 1 encompasses a genus of anti-EpCAM polypeptides.
In support of the claimed genus of variants, the specifications disclose 13 specific variants, whereby the CDRs 1-3 are defined with 100% identity and no substitutions (specifications, pg. 31; see also instant claim 2). Applicants attempt to provide a consensus sequence of the H3-CDRs (see drawings, Fig. 1), and also suggest alternative amino acids that may be used at specific residues (specs., pg. 17, para. 0077). However, it is not clear what underlies the suggested substitutions as the alternative embodiments were not reduced to practice to demonstrate that they maintain binding to the target; no guidance it provided to the skilled artisan as to which substitutions to choose to incorporate. Further, the attempted consensus sequences, and potential alternative residue substitutions are not claimed; rather, the claims encompass numerous potential substitutions beyond those described in the specifications. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. When viewing the alignment of the 13 claimed H3-CDRs (see Fig. 1), it does not appear that even a single amino acid residue is conserved across all 13 embodiments; thus there is not a consensus sequence for the H3-CDR sequence.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1).
Further, it is known that the heavy chain CDR2 and CDR3 regions contain most of the residues that have a major contribution to the binding free energy of the antigen binding domain (Dondelinger et al., 2018; pg. 8, col. 1, para. 2 – col. 2, para. 1). Regarding single domain antibodies (sdAbs), which comprise only a VHH heavy chain, comprising the 3 heavy chain CDRs, Sheriff et al., (1998) teaches that while the usual conception is that an antibody (or receptor) envelops its ligand, with sdAbs derived from camels, the antibody inserts a part of its binding surface deeply into a pocket on the surface of the ligand; and that about 70% of the total surface area buried in this interaction is contributed by CDR3 (pg. 735, col. 2, para. 2 – col. 3, para. 1). Thus, the CDR3 of sdAbs is of considerable importance to the functionality of the sdAb with regard to specificity and affinity.
Thus, the hyper-variable regions, comprising the complementary set of CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies, or antigen binding polypeptides, based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the claimed embodiments, in which alternative mutations were made, which were reduced to practice; nor do they identify the shared structural properties of the variants, such as the CDR residues or humanized framework regions, that would define the genus beyond the desired functionality. Currently the essential property of binding EpCAM is imparted by the specific VHH variable domain embodiments that have been reduced to practice; and that accounts for only 13 examples out of a multitude of potential embodiments as claimed. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding the same epitope of EpCAM should be disclosed. Further, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 90%, at least 95%, or at least 99%” sequence identity to a selected sequence, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (variable domains with 90%, 95% or 99% identical sequences) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an embodiment species comprising an H3-CDR with < 90% in shared sequence identity to any of claimed SEQ ID NOs: 27-39, would still bind EpCAM; or conversely, that antibodies with > 99% sequence identity, but comprising a deleterious mutation in the H3-CDR region would lose functional binding to EpCAM.
Regarding the mixing and matching of the H1-CDRs, H2-CDRs and H3-CDRs; it is well-known in the art that specificity of an antibody-like binding peptide stems from the interaction of the CDRs, and the CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not reasonably be expected to confer the same binding properties or even the same binding target when combined with two CDRs from other antibodies or VHHs. Here, the specifications do not provide any guidance for mixing and matching the different claimed CDR regions, and a skilled artisan cannot expect that mixing and matching the different H1-CDRs with the different H3-CDRs (all H2-CDRs are the same sequence) would result in a functional binding polypeptide. For example, Silence et al., (from IDS, cite No. 4; WO 2006122825; published 11/23/2006) teaches single domain antibodies (sdAb; i.e. nanobodies) which bind von Willebrand Factor (vWF; abstract). Silence teaches one such binder is that of species 12A2, of SEQ ID NO: 71 (pg. 181, Table 11). Silence SEQ ID NO: 71 comprises 3 CDRs as listed in instant claim 1; the H1-CDR of instant SEQ ID NO: 12, the H2-CDR of instant SEQ ID NO: 14 and the H3-CDR of instant SEQ ID NO: 30, with 100% sequence identity, specifically when defined using IMGT numbering scheme. Thus, Silence et al. teaches a sdAb polypeptide binding construct encompassed by instant claim 1, with 100% identity; and yet it binds vWF, and not EpCAM. Silence et al. provides a clear example from the art that a skilled artisan cannot mix and match CDRs with a predictable outcome for maintaining binding to the target antigen. In this case, the mixing and matching of CDRs results in a sdAb that binds an entirely different antigen.
“The purpose of the written description requirement is to ‘ensure that the scope of the
right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s
contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli
Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D.
Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description
requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed
invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir.
1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the
problem to be solved while claiming all solutions to it and … cover any compound later actually
invented and determined to fall within the claim’s functional boundaries- leaving it to the
pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli
Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
In view of the uncertainty of randomly substituting amino acid residues in the critical H3-CDR, the example of mixing and matching the claimed CDRs whereby the resulting polypeptide loses EpCAM antigen specificity, and the lack of a representative number of examples of the claimed genus, claims 1 and 4-6 are rejected for lack of adequate written description support. Claims 3 and 7-22 are also rejected as they depend from rejected claim 1, yet fail to resolve the issues of descriptive support over the scope of the claimed anti-EpCAM polypeptides.
Allowable Subject Matter
Claim 2 is objected to as being dependent upon a rejected base claim 1. However, the 13 specific embodiments of claim 2, whereby each embodiment has a specific set of 3 corresponding CDRs, have been searched and are free of the prior art. Thus the embodiments of claim 2 would otherwise be allowable. The 13 heavy chain variable domains of SEQ ID NOs: 40-52, of claim 3, incorporate the corresponding CDR sets of claim 2, and therefore would also be allowable if they depend from the embodiments of claim 2, and thus necessarily require the specific sets of 3 CDRs of claim 2.
Conclusion
No claims are allowed. Claim 2 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644