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 .
Election/Restriction
Applicant’s election without traverse of species comprising, consisting of, or consisting essentially of a VH/VL pair for anti-HLA-G and anti-CD3 of SEQ ID NOs: 192 and 220 and 413 and 422, respectively, which comprise six nondegenerate CDRs for each binding domain, in the reply filed on 27JAN2026 is acknowledged.
Claims 4-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. In the instance of claim 4, based on Applicant’s election of VH/VL pair for anti-CD3 of SEQ ID NOs: 413 and 422, respectively, which comprise six nondegenerate CDRs, the LCDR2 is not listed in the SEQ ID NOs: 396-400 of claim 4 (i.e., SEQ ID NO: 396 is the closest sequence within SEQ ID NO: 422 with 89.2% query match, see OA.APPENDIX) and therefore is withdrawn from further consideration. Election was made without traverse in the reply filed on 27JAN2026.
Claim Status
Claims 4, 11-13, and 15 have been amended.
Claims 16-34 have been canceled.
Claims 1-15 are pending in the instant application (i.e., Claim(s) 1 is/are independent).
Claims 4-9 are withdrawn.
Claims 1-3 and 10-15 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2021/036838, filed 10JUN2021, which claims the benefit of US Provisional Patent Application No. 63/037985, filed 11JUN2020. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 18JUN2024 and 02OCT2025 is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (see for example ¶00594 or ¶00624) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in ¶00594 and ¶00624.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Claim 12 is objected to because of the following informalities:
Claim 12 contains a typographical error: “SEQ ID NO: 204-228” should be corrected to “SEQ ID NOs: 204-228” in line 6 of the claim for the purposes of consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 10-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3 and 10-13 recite the open language “comprising,” which does not exclude additional unrecited elements and also recite the closed language “consisting of,” which does not allow for additional unrecited elements, and in the instance of claim 12, further recites the middle ground language “consisting essentially of” which limits the scope of the claim to the specified materials and those that do not materially affect the basic and novel characteristics of the claimed invention (see MPEP § 2111.03). Therefore, it is unclear how the scope of claims 3 and 10-13 allow for additional unrecited elements and how they can also exclude additional unrecited elements. One of ordinary skill in the art would not be reasonably apprised of the scope of patent protection sought. For example, it is unclear in regards to claim 12 which recites “…comprising, consisting of, or consisting essentially of a VH set forth in SEQ ID NOs: 170-200…”, if the patent protection sought is limited to i) the full-length of SEQ ID NOs: 170-200 with or without amino acid residues at either or both ends (i.e., comprising), ii) the full-length of SEQ ID NOs: 170-200 and nothing more or less (i.e., consisting of), or iii) the full-length of SEQ ID NOs: 170-200 with additional components that would not materially affect the basic and novel characteristics. Examiner notes that in this instance, the basic and novel characteristics are not disclosed in the specification, and therefore, “consisting essentially of” will be construed as equivalent to “comprising.” Claims 14-15 are also rejected since they depend from claim 13, but do not remedy this deficiency.
Regarding claim 14 (subsection “t”), the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Written Description
Claims 1-3 and 10-15 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.
Scope of the claimed genus:
Applicant has broadly claimed a bispecific antigen binding construct comprising a binding domain capable of binding to an HLA-G epitope and an additional binding domain capable of binding to a second epitope. The broadest claims do not require the bispecific construct to have any function apart from binding HLA-G and essentially any other epitope, with dependent limitations adding additional functional limitations, such as, the additional binding domain being capable of binding to CD3ε epitope (i.e., claim 2), the CD3ε epitope comprising or consisting of SEQ ID NO: 629 (i.e., claim 3), or the HLA-G epitope comprising or consisting of SEQ ID NO: 342 (i.e., claim 10). No claims recite any specific or particular structure of the bispecific construct that gives rise to the specific binding functions, with exception of claim 11, which recites a potential structure of the binding domain for binding to HLA-G, but does not recite a specific structure of the second binding domain and claim 12, which recites 31 VH sequences and 25 VL sequences for the HLA-G and six sequences each for the VH and VL of the CD3ε binding domains of the bispecific antigen construct; however, does not recite the specific pairs which maintain the function of binding each respective binding domain. Claims 13-15 are also rejected since they depend from claim 1 but do not remedy this deficiency.
State of the relevant art:
Artisans are well aware that knowledge of a given antigen (for instance a specific epitope of HLA-G or CD3ε or essentially any other epitope) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
In the instance of a bispecific antibody, it is well known in the art, that such a construct comprises two pairs of VH/VL regions (i.e., one pair for each binding domain) and each VH/VL pair consists of six CDRs for a total of 12 CDRs (Brinkmann, et al., MABS, 2017, 9, 182-212, see p 183, col 1, ¶1 and Fig 1-2). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves. Furthermore, the pairing propensity of any two given germlines depends to a large extent on the sequence and conformation of HCDR3, which is highly variable and if HCDR3 is fixed, different VH/VL pairs can result in significant stability differences (Chiu, et al., Antibodies, 2019, 8, 1-80, Section 2.1.3). Therefore, the art supports that the nondegenerate CDR sequences for each antigen binding domain and the specific pairing of the VH and VL sequences for each antigen binding domain are necessary structural features to maintain functional binding.
Accordingly, the skilled artisan would be unable to envisage the structure of an antibody that binds HLA-G and any particular epitope thereof a priori given the current state of the antibody arts.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
To support such broad claims, the specification teaches bispecific constructs comprising a HLA-G binding domain and a CD3ε binding domain with the potential to change the CD3ε binding domain to a CD16, NKp46, or NKp30 binding domain for engaging NK cells, dendritic cells, monocytes, or macrophages (Table S). In the instance of the HLA-G binding domain, the specification teaches a specific VH sequence paired with any VL sequence of SEQ ID NOs: 204-228, for example, SEQ ID NOs: 170/204-228,… 200/204-228 (¶00166-00196); a combination of HCDR1-2-3-LCDR1-2-3 of for example, SEQ ID NOs: 18, 54, 76,105, 128, and 149 (i.e., a specific combination of six nondegenerate CDRs) (¶00198-00199); VH and VL sequences having 85-99.1% identity to the illustrative sequences (¶00201-00205); a specific HC sequence paired with any LC sequence of SEQ ID NOs: 300-330, for example, SEQ ID NOs: 232/300-330, 233/300-330,…. 296/300-330 (¶00208-00269); and more specific HC/LC pairs of SEQ ID NOs: 232/300, 233/301,… 262/330 or SEQ ID NOs: 266/300, 267/301,… 296/330 (¶00270-00271). Although there is support for a specific combination of six nondegenerate CDRs and a general combination of VH/VL sequences each comprising the specific combination of six nondegenerate CDRs for the HLA-G binding domain; it is unclear whether every VH sequence would pair with each VL sequence and maintain HLA-G binding function and furthermore, there is no support for any additional binding domain of the bispecific antigen binding construct. With regards to the CD3ε binding domain the specification discloses a specific VH sequence paired with any VL sequence of SEQ ID NOs: 422-427, for example, SEQ ID NOs: 413/422-427,… 418/422-427 (¶00338-00343); a combination of HCDR1-2-3-LCDR1-2-3 of for example, SEQ ID NOs: 354, 371, 379, 388, 396 (i.e., Kabat numbering), or SEQ ID NOs: 404 or 346, 362, 379, 388, 396, and 404 (i.e., Chothia numbering) (i.e., a specific combination of six nondegenerate CDRs) (¶00345-00346); and VH and VL sequences having 85-99.1% identity to the illustrative sequences (¶00347-00351). The specification further discloses antigen binding domains to CD16, NKp46, and/or NKp30 (¶00352-00553). Although the claims are drawn to a bispecific construct comprising essentially any HLA-G binding region and essentially any second antigen-binding region, the experimental data teach a single bispecific structure. In Example 3, a singular HLA-G x CD3 bispecific DART-Fc structure is taught, comprising two polypeptide chains comprising anti-CD3 VL (SEQ ID NO: 422)-linker (GGGSGGG)-anti-HLA-G VH (SEQ ID NO: 192)-EEE mutated hinge-Fc and anti-HLA-G VL (SEQ ID NO: 220)-linker (GGGSGGG)-anti-CD3 VH (SEQ ID NO: 413)-Fc with RRR mutations (¶00624). Therefore, given the immense breadth of the claims and the depth and diversity of the antibody repertoire as described above, such a disclosure would not reasonably be considered representative of the genus: a bispecific antigen binding construct, which is only described by its binding target.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description 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.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.” Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed HLA-G and essentially any additional epitope binding activity.
The specification provides support for a singular example of a bispecific antigen binding construct, which functions to specifically bind HLA-G and CD3ε, and comprises two polypeptide chains comprising anti-CD3 VL (SEQ ID NO: 422)-linker (GGGSGGG)-anti-HLA-G VH (SEQ ID NO: 192)-EEE mutated hinge-Fc and anti-HLA-G VL (SEQ ID NO: 220)-linker (GGGSGGG)-anti-CD3 VH (SEQ ID NO: 413)-Fc with RRR mutations (¶00624). In this instance, the specification supports a specific VH/VL pair for each binding domain, each comprising six nondegenerate CDRs. It is noted that in Example 3, a dual-affinity re-targeting (i.e., DART) with an Fc domain structure is supported in the specification (¶00624), which is expected to perform better (i.e., maintains potency in vitro and in vivo with reduced aggregation or increased stability) than for example a bispecific T cell engager (i.e., BiTE) construct (Wang, et al., Antibodies, 2019, 8, 1-30, Section 2.1.1); however this particular structure is not currently claimed. Therefore, the specification lacks support for the breadth of a HLA-G x any second antigen bispecific antigen binding construct.
Claim analysis:
In this instance, the prior art supports a specific combination of six nondegenerate CDRs for each antigen binding domain and a specific combination of VH/VL pairing for each antigen binding domain. As presently written, the claims recite that the bispecific antigen binding construct comprising a binding domain to HLA-G and an additional binding domain to essentially any other epitope/target functions to bind said targets. However, the specification and working examples fail to disclose the breadth of structures (i.e., specific combinations of six nondegenerate CDRs, specific VH/VL pairs for each binding domain of the bispecific constructs, or format of the constructs with exception of Example 3), encompassed by the language of the instant claims which will have the same function (i.e., binding HLA-G and any additional antigen). Therefore, as presently written, the claimed broad genus of bispecific antigen binding construct lacks adequate written description because there does not appear to be any correlation between the structure (with exception of Example 3) and the ability to bind the epitope of interest. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of bispecific antigen binding construct that binds HLA-G and essentially any other epitope, at the time the instant application was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 10-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,208,487 B2, herein referred to “the ‘487 patent” in view of WO 2019/202041 A1 (F. HOFFMANN-LA ROCHE AG, et al., 24OCT2019, included in IDS), herein referred to as “’041” and WO 92/22653 (GENENTECH, INC, et al., 23DEC1992); herein referred to as “’653.”
The issued claims of the ‘487 patent recite: An antibody that specifically binds to human HLA-G, comprising a VH and VL wherein a) the VH comprises: i) HCDRs1-3 of SEQ ID NOs: 7, 44, and 93 according to Chothia; or ii) HCDRs 1-3 of SEQ ID NOs: 25, 65, and 93 according to Kabat; and b) the VL comprises: i) LCDRs1-3 of SEQ ID NOs: 118, 138, and 155 according to Chothia and Kabat (i.e., claim 1). The antibody of claim 1, comprising a VH sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 192 and a VL sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 220 (i.e., claim 2, see OA.APPENDIX). In this instance claims 1 and 2 of the ‘487 patent are 100% query match to the HCDRs1-3, LCDRs1-3, VH and VL sequences of claims 11 and 12 of the instant application. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient (i.e., claim 7). The pharmaceutical composition of claim 7, further comprising an effective amount of at least one of the following: a) an anti-ILT2 antibody,….g) an anti-PD-L1 antibody, h) an anti-PD1 antibody,… and/or x) ADCC capable therapies… (i.e., claim 8). The pharmaceutical composition of claim 8, further comprising one or both of a) an antibody to an immune inhibitory receptor or ligand and/or b) an antibody to an immune stimulatory receptor or ligand (i.e., claim 9).
However, they do not claim: a bispecific construct comprising HLA-G and any additional binding domain; wherein the additional binding domain is CD3ε; the HLA-G epitope of SEQ ID NO: 342; the CD3ε of SEQ ID NO: 629; or the VH and VL of the CD3ε binding domain of SEQ ID NOs: 413 and 422.
Nevertheless, ‘041 teaches multispecific antibodies that bind to HLA-G and to a T cell activating antigen of CD3 (see entire document, specifically see abstract, Fig 7-12, claim 1). Furthermore, ‘041 teaches bispecific constructs binds specifically HLA-G (i.e., does not have cross-reactivity with other MHC I molecules) and is able to target CD3 on T cells, which forces a temporary interaction between the target HLA-G-positive cell (i.e., pancreatic, breast, skin, colorectal, gastric, and ovarian tumors) and a T cell causing crosslinking of the T cell receptor and subsequent activation of any cytotoxic T cell and subsequent lysis of the HLA-G-positive cell without off-target effects (i.e., cancer therapy) (p 1-3). ‘041 additionally teaches variants of the HLA-G and CD3 binding domains, which improve the binding affinity and/or other biological properties of the bispecific antibody (p 123, lines 19-21).
Additionally, ‘653 teaches humanization of antibodies and incorporation of for example a humanized anti-CD3 antibody into a bispecific construct, specifically Fig 5 shows the amino acid sequence of known anti-CD3 monoclonal antibody, UCHT1 and a humanized variant thereof (i.e., the VH and VL of UCHT1 consist essentially of SEQ ID NOs: 413 and 422 of the instant application).
It would have been obvious to artisans to modify the issued product of an antibody that specifically binds to HLA-G comprising a VH and a VL comprising the HCDRs1-3 and LCDRs1-3 amino acid sequences set forth in specific SEQ ID NOs as claimed by the ‘487 patent to include an additional binding domain, such as human CD3ε, wherein the CD3ε antigen binding domain consists essentially of the VH and VL of known anti-CD3ε antibody, UCHT1, as taught by ‘041 and ‘653. This is because ‘041 and ‘653 teaches that a specific HLA-G x CD3ε bispecific complex reduces cross-reactivity with other MHC I molecules and allows for activation of cytotoxic T cells to kill HLA-G-positive cells which are present in several forms of cancer and because the UCHT1 anti-CD3ε antibody has been known since 1992 and therefore has been widely used to study and/or activate human T cells. One would have been motivated to do so, given the direction by the open language of the ‘487 patent that allows for incorporation of additional amino acid sequences before and/or after a VH and VL comprising the amino acid sequences HCDRs1-3 and LCDRs1-3 of the specified SEQ ID NOs. There would have been a reasonable expectation of success, given the knowledge that by modifying the antibody that specifically binds HLA-G taught by ‘487 by incorporating a secondary binding domain of CD3ε having the VH/VL consisting essentially of UCHT1 VH/VL would lead to a bispecific HLA-G x CD3ε, which would be useful in targeting HLA-G-positive tumors with an effective CD3ε T cell activator, as taught by ‘041 and ‘653.
Although ‘487, ‘041, and ‘653 are silent with regard to the bispecific antigen binding construct comprising a binding domain capable of binding to an HLA-G epitope of SEQ ID NO: 342 and a CD3ε epitope of SEQ ID NO: 629 in claims 3 and 10, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the HLA-G x CD3ε binding domains of the specific sequences taught by ‘487, ‘041, and ‘653 would have the claimed properties recited in claims 3 and 10.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/202041 A1 (F. HOFFMANN-LA ROCHE AG, et al., 24OCT2019, included in IDS), herein referred to as “’041.”
‘041 teaches multispecific antibodies that bind to HLA-G and to a T cell activating antigen of CD3 (see entire document, specifically see abstract, Fig 7-12, claim 1). Furthermore, ‘041 teaches bispecific constructs binds specifically HLA-G (i.e., does not have cross-reactivity with other MHC I molecules) and is able to target CD3 on T cells, which forces a temporary interaction between the target HLA-G-positive cell (i.e., pancreatic, breast, skin, colorectal, gastric, and ovarian tumors) and a T cell causing crosslinking of the T cell receptor and subsequent activation of any cytotoxic T cell and subsequent lysis of the HLA-G-positive cell without off-target effects (i.e., cancer therapy) (p 1-3). ‘041 additionally teaches variants of the HLA-G and CD3 binding domains, which improve the binding affinity and/or other biological properties of the bispecific antibody (p 123, lines 19-21).
Therefore, the prior art anticipates the invention as presently claimed.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/043899 A1 (Invectys, et al., 05MAR2020), herein referred to as “’899.”
‘899 teaches a multispecific CAR construct which comprises at least two different antigen binding domains,…, wherein at least one of the antigen binding domains specifically binds HLA-G isoforms (see entire document, specifically see claim 15).
Therefore, the prior art anticipates the invention as presently claimed.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/123627 A1 (STC Biologics, Inc, et al., 20JUL2017), herein referred to as “’627.”
‘627 teaches a platform for bispecific targeting agents, wherein one arm comprises a single chain antibody or antibody that binds HLA-G and a second armbinds a second target antigen (see entire document, specifically see claims 2 and 18).
Therefore, the prior art anticipates the invention as presently claimed.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2016/154585 A1 (Sentman, et al., 29SEP2016), herein referred to as “’585.”
‘585 teaches anti-MICA antibody or antigen binding fragment, CAR, or BiTE, or other fusion comprising an antibody or antigen binding fragment or ligand which specifically binds to an antigen expressed on an immune effector cell selected from CD3,….HLA-G,….and CD83 (see entire document, specifically see claims 1, 2, and 13).
Therefore, the prior art anticipates the invention as presently claimed.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/207775 A1 (Invectys, et al., 07DEC2017), herein referred to as “’775.”
‘771 teaches an anti-HLA-G antibody, wherein the antibody is a full-length antibody, an antigen-binding fragment thereof, preferably a scFv or a bispecific antibody (see entire document, specifically see claims 4-5).
Therefore, the prior art anticipates the invention as presently claimed.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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