DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/28/2026 has been entered.
Claims 1-11 are pending.
3. Claim 1 is objected to because of an apparent typographical error in the term “connexin26” where it appears that “connexin 26” was intended. Appropriate correction or clarification is required.
4. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
5. Claims 1-11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claim 1 is indefinite because of the following inconsistencies:
claim 1 recites an “antigen binding protein […] capable of binding an antigen selected from the group” which includes “Dengue Virus 1 (DENV1) FAB 14C10” and “a synuclein intrabody.” “FAB 14C10” is itself a specific antigen binding protein capable of binding dengue virus serotype 1, while “intrabody” refers to a type antigen binding proteins capable of binding intracellular proteins inside a living cell. Therefore, it is unclear whether the claim is directed to proteins capable of binding the above antigen binding proteins, or to proteins capable of binding the targets of the above antigen binding proteins.
(ii) Claim 1 is further indefinite in the recitation of “immunoglobulin binding domain,” because it is unclear whether it refers to a domain binding to an immunoglobulin (similarly to “antigen binding domain” binding to an antigen), or to an antigen binding domain of an immunoglobulin.
(iii) Claim 1 is further indefinite in the recitation of a generic “antigen binding domain” which “comprises a heavy chain variable region (VH), wherein the VH comprises a heavy chain CDR-3 having a carboxyl terminus, and a heavy chain framework 4 region (VH-FR4).” A person of ordinary skill in the art would readily understand how VH, CDR-3 and VH-FR4 are defined in an antigen binding domain of an immunoglobulin; in contrast, it is unknown what constitutes VH, CDR-3 or VH-FR4 in an antigen binding domain which is not a part of an immunoglobulin.
(iv) Claim 1 is further indefinite in the recitation of “the last amino acid residue of the carboxyl terminus of the heavy chain CDR-3” (see subsection 3(ii) of the previous Office Action). Applicant amended the claim to specify that the VH residues are numbered according to Kabat numbering, but it is still unknown how “the last amino acid residue of the carboxyl terminus of the heavy chain CDR-3” is defined.
(v) Claims 2-11 are indefinite, because they encompass the indefinite limitations of the claim(s) on which they depend.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
6. The following is a quotation 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.
7. Claims 1-11 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contain(s) subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the antibody defined as “FAB 14C10” is required to make and use the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, first paragraph, may be satisfied by a deposit of the cell line which produces this antibody. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the material has been deposited under the terms of the Budapest Treaty would satisfy the deposit requirement made herein.
In addition to the conditions of the Budapest Treaty, applicant is required to provide assurance that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent in U.S. patent applications.
8. Claims 1-11 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for an antigen binding protein possessing the structural features recited in claim 1, wherein the antigen binding protein is “FAB 14C10” capable of binding dengue virus serotype 1,
does not reasonably provide enablement for an antigen binding protein possessing the structural features recited in claim 1, wherein the antigen binding protein is generically recited as “capable of binding” any of the other antigens recited in claim 1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims without undue experimentation.
The claims encompass in their breadth any antigen binding protein capable of binding any of the targets recited in claim 1, which include proteins as wells as a pathogen (Burkholderia mallei) and a plant (Prunus dulcis). A person skilled in the art would be aware that each protein contains multiple epitopes, an organism such as a pathogen or a plant contains multiple proteins as well as non-protein antigens, and each epitope may be recognized by multiple antigen binding proteins of unrelated structural and functional properties.
The present specification at [00188] provides the following disclosure:
“The solubility, aggregation and functional properties of the anti-PD-1 scFv were all improved by the L124G and T126R mutations. As shown in FIG. 15, a wide array of scFv's and diabodies contain both Leu and Thr residues at analogous positions to anti-PD-1 scFv residues Leu 124 and Thr 126 (the scFv's in FIG. 15A have known structures, while those in FIG. 15B have unknown structures). Moreover, additional Aggrescan 3D based analyses of the scFv's presented in FIG. 15A revealed that the conserved Leu and Thr residues are in APR regions. Thus, a number of previously described scFv's contain APRs that are formed, in part, by the conserved Leu and Thr residues. The scFv's listed in FIG. 15 include those targeting HIV GP120, alpha synuclein, VEGF and TNF alpha. Therefore, in some embodiments, mutations of the conserved Len and Thr residues, to those analogous to the ones described herein are used to enhance the properties, e.g. solubility and functional properties, of a range of important scFv molecules and other antigen binding proteins.”
Based on this disclosure, a person skilled in the art would readily understand that Gly and/or Arg at positions specified in claim 1 might improve solubility, aggregation and/or functional properties of immunoglobulin-based antigen binding proteins containing Leu and/or Thr residues at positions analogous to Leu-124 and Thr-126 of nivolumab-based anti-PD-1 scFv described in the Examples of the present application. There does not appear to be any basis, either in the knowledge in the art or in present disclosure, to infer that Gly and/or Arg at positions corresponding to Kabat positions 124 and 126, respectively, would have a positive effect on the properties of antigen-binding proteins which do not comprise Leu and Thr, respectively, at these positions.
While it is routine in the art to make specific amino acid substitutions in proteins, the utility of the present invention is in potentially improved properties of immunoglobulin-based antigen binding proteins as a result of the specified substitutions. Since it is unpredictable whether these substitution would have a positive effect on proteins which do not contain Leu and Thr at positions corresponding to Kabat positions 124 and 126, respectively, the entire scope of experimentation required to improve the properties of the generically recited binding proteins by performing the specified substitutions is left to those skilled in the art, the present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to invent such methods.
9. Claims 1-11 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contain(s) 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, at the time the application was filed, had possession of the claimed invention.
Specifically, the inventor or a joint inventor is not in possession of an antigen binding protein capable of binding an antigen selected from the group consisting of PD-1, connexin26, fibronectin ED-B, Dengue Virus 1 (DENV1) FAB 14C10, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain, cytomegalovirus Glycoprotein B, a synuclein intrabody, triggering receptor expressed on myeloid cells-like transcript-1 (TLT-1), human immunodeficiency virus-1 (HIV1) gp120, Burkholderia mallei, murine laminin, vascular endothelial growth factor 2 (VEGFR2), ivermectin, tumor necrosis factor alpha (TNFa), myostatin, vascular endothelial grown factor 165 (VEGF165), Prunus dulcis, and Xanthomonas pthA.
It is well established in the art that the antigen-binding properties of antibodies are primarily, although not exclusively, determined by the amino acid sequences of their CDR regions, and that antibodies having a broad variety of CDR sequences can bind to the same epitope, compete with each other, and possess essentially the same antigen-binding and other functional properties See e.g. Khan et al. (2017), Konitzer et al. (2017), or Parola et al. (2018).
The written description requirement for a claimed genus may be satisfied either through sufficient description of a representative number of species, or by disclosure of relevant, identifying characteristics, i.e., structure or other properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics. MPEP 2163(II)(A)(3)(a)(ii).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. For inventions in an unpredictable art, written description of a genus which embraces widely variant species must adequately reflect the structural diversity of the claimed 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. MPEP 2163(II)(A)(3)(a)(ii).
The specification discloses in Figure 15 a single exemplary antibody for each of the recited antigens. As amply demonstrated by the references cited above, it is impossible for the skilled artisan to even estimate the size of the genus of possible CDR sequences of antibodies which can bind to the same epitope or compete for binding with the specified antibody, let alone visualize or recognize the identity of such sequences. As such, the outer boundary of the claimed genus is unknown, both in terms of size and structural diversity. Thus, neither applicant’s disclosure nor the knowledge in the art allows the skilled artisan to predict the undisclosed members of the genus. Accordingly, the disclosed antibodies are not representative of the structural diversity of the claimed genus.
Further, there is no “known or disclosed correlation” between the function of binding to a particular antigen, and the structural features which must be possessed by an antibody to accomplish this function. The specification does not disclose such correlation, and the teachings of the references cited above make it abundantly clear that at the present state of the art a skilled artisan cannot visualize or recognize the vast genus of possible CDR sequences which would endow an antibody with the recited properties. It is impossible for the skilled artisan to know in perfect detail the physiological and genetic backgrounds of all immune systems capable of producing antibodies, nor their prior immunological exposure. For example, Van Regenmortel (2018) highlights the difficulties inherent in immunological “inverse problems,” which start with the result (e.g. binding to an epitope) and then try to guess the multiple causes (i.e. structures) that could have produced it. According to Van Regenmortel, the extent of the immune system degeneracy, including the ability of numerous different antibodies and T cell receptors to bind to the same epitope, is still underappreciated.
To summarize, present specification does not describe a representative number of species or structural features common to the species encompassed by generic claims, nor is there a known or disclosed correlation between function and structure; therefore, the specification fails to satisfy the written description requirement of 35 U.S.C. 112(a).
10. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
11. Claims 1-4 and 6-11 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Georgiev et al. (US 20230348571).
Applicant's claim for domestic priority under 35 U.S.C. 119(e) is acknowledged. The Examiner was unable to identify adequate support under 35 U.S.C. 112 for antigen binding proteins capable of binding any of connexin26, fibronectin ED-B, Dengue Virus 1 (DENV1) FAB 14C10, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain, cytomegalovirus Glycoprotein B, a synuclein intrabody, triggering receptor expressed on myeloid cells-like transcript-1 (TLT-1), human immunodeficiency virus-1 (HIV1) gp120, Burkholderia mallei, murine laminin, vascular endothelial growth factor 2 (VEGFR2), ivermectin, tumor necrosis factor alpha (TNFa), myostatin, vascular endothelial grown factor 165 (VEGF165), Prunus dulcis, or and Xanthomonas pthA in provisional application USSN 63/261,090 upon which priority is claimed. Consequently, presently pending claims have been accorded the priority of the filing date of PCT/US2022/076309, i.e. 09/12/2022. Should Applicant disagree with the above Examiner’s determination, it is incumbent upon Applicant to provide a showing that specifically supports the indicated claim limitations.
Georgiev teaches anti-SARS-CoV-2 antibody clone 4327, which comprises VH of SEQ ID NO: 7510 (Table 2). Georgiev’s SEQ ID NO: 7510 comprises VH-FR4 comprising instant SEQ ID NO: 43 (see SCORE). The antibody may be in scFv format (e.g. [0060]). Accordingly, Georgiev anti-SARS-CoV-2 antibody clone 4327 is within the scope of instant claims 1-4.
Georgiev further teaches conjugating the antibodies to a detectable agent such as a fluorescent agent (e.g. [0516] - [0520]), and including them in a composition (e.g. [0083]), thereby anticipating claims 6-8. Since the antibodies are recombinantly produced, polynucleotides, expression vectors and host cells are inherent in teachings of the antibodies, i.e. claims 9-11 are anticipated.
12. 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 of this title, 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.
13. Claims 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Georgiev et al. (US 20230348571) in view of Kelley et al. (US Patent No. 10407510, of record).
As explained in section 11 above, Georgiev teaches an antibody within the scope of instant claim 1, and conjugates of the antibody with detection promoting agents.
Although Georgiev may not specifically exemplify an antibody with a C-terminal cysteine, addition of cysteine to C-termini of antibody polypeptide chains was known and routinely used in the art to facilitate conjugation of various detection or therapeutic moieties. For example, Kelley teaches and claims antibody conjugates comprising an engineered cysteine at the C-terminus of heavy or light chain (e.g. claims 1, 41 and 44-47).
The motivation to add cysteine to the C-terminus of Walker’s antibody would have been provided by Walker’s teachings of antibody conjugates in combination with art-recognized advantages of using a free sulfhydryl group of cysteine for covalent attachment of certain chemical groups. The expectation of success would have been provided by the routine nature of the procedure and by the recognition that a C-terminal addition is less likely to interfere with protein structure and function, as compared to addition at an internal site.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
14. The following prior art is cited of record but not presently relied upon:
US Pat. Pub. No. 20230331825 teaches a SARS-CoV-2-binding protein comprising SEQ ID NO: 17575, which comprises instant SEQ ID NO: 43 (see SCORE).
15. Conclusion: no claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 9 AM - 5:30 PM.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644
