DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112(b)
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 1-6 and 13-26 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.
Claim 1 line 6-8 recite “wherein the binding molecule has increased capability of hexamerization on a cell surface, and/or increased capability of engaging C1q, and wherein the antigen binding domain comprises a VH region and a VL region contained in”. The comma before “and wherein the antigen binding domain comprises […]” causes confusion because the other limitations, for example, “the antigen binding domain is monovalent” is separated from the next limitation by a semi-colon. In lines 6-8, it is unclear whether the antigen binding domains must comprise a VH and VL region contained in the recited sequences only if increased capability of engaging C1q is selected. In other words, increased capability of hexamerization and increased capability of engaging C1q are alternatives, but do the antigen binding domains have to comprise a VH and VL region contained in the recited sequences regardless of which of those alternative increased capabilities are selected? If so, the Office suggests replacing the comma before “and wherein the antigen binding domain comprises […]” with a semi-colon. For the purpose of compact prosecution, the claim is interpreted as requiring the VH and VL regions of the antigen binding domain be found within the recite sequences regardless of which increased capability the binding molecule possesses.
Claims 1, 14, and 15 recite the Fc region comprises K248E and T437R mutations. As evidenced by Presta (US 6,737,056 B1; Published: May 18, 2004) not all Fc regions comprise K248 and T437 according to EU numbering.
PNG
media_image1.png
598
465
media_image1.png
Greyscale
It is unclear of which antibody isotype and species the Fc region recited must be.
Claims 1, 14, and 15 recite “wherein the antigen binding domain comprises a VH region and a VL region contained in a heavy chain and a light chain respectively selected from” then recites full length heavy and light chains. The claims require only a subsequence (i.e. the VH and VL regions) within the full heavy and light chains, but the claim does not indicate which subsequences are required. More specifically, it is unclear what subsequence Applicant considers the VH and VL regions. To add to the confusion, SEQ ID NOs: 259 and 260 are identical and SEQ ID NOs: 257 and 258 are near identical, differing at positions 248 and 437 according to EU numbering which are typically outside of the region considered the VH. Paragraph 0063 defines VH and VL regions, but does not clearly indicate which amino acid residues are encompassed in the VH and VL regions.
For the purpose of compact prosecution, claim 1 is interpreted as requiring the antigen binding domain comprises the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 334.
For the purpose of compact prosecution, claims 14 and 15 are interpreted as requiring the antigen binding domain comprises the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 332.
Additionally, claims 1, 14, and 15 comprise the limitation “(RE mutations)”. The parenthetical makes unclear whether “RE mutations” is the name for the combined K248E and T437R mutations or if any RE mutations are an acceptable alternative. If RE mutations is the term for the combined K248E and T437R mutations, why is it plural? For the purpose of compact prosecution, “(RE mutations)” is interpreted as the name for the combined K248E and T437R mutations.
Claims 1 and 14-16 recite that the antigen binding domain is monovalent. It is unclear how an antigen binding domain could be anything, but monovalent. Considering a monoclonal antibody which comprises two Fab antigen binding site, the overall antibody is bivalent, but each Fab antigen binding site is monovalent. For the purpose of compact prosecution, the claims are interpreted as reciting that the overall binding molecule is monovalent.
Claims 3 and 19 recite “the antigen” in line 3. “[T]he antigen” lacks antecedent basis. It is unclear to which antigen “the antigen” refers. No antigen is recited in claims 1, 2, or 14, from which claims 3 and 19 depend.
Claims 5 and 20 recite that the binding molecule is a fragment of an antibody. It is unclear how the binding molecule, which requires an Fc region as recited in claims 1 and 14, could be a fragment of an antibody. For the purpose of compact prosecution, the antigen binding domain is interpreted as being an antibody fragment.
The preamble of claim 26 recites a method of making the binding molecule of claim 1, while the body of the claim encompasses expressing a polynucleotide encoding a fragment of the binding molecule. Given the disconnect between the preamble and the body of claim 26, it is unclear whether the claim is to a method of making the binding molecule of claim 1 or a fragment of the binding molecule of claim 1. For the purpose of compact prosecution, claim 26 is interpreted as a method of making the binding molecule of claim 1 – not a fragment.
Claims 2-6, 13, 23, 24, 25, 26 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claims 17-22 are rejected for depending from claim 14 and failing to remedy the indefiniteness.
Claims 16 are rejected for depending from claim 15 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 3, 5, and 18-20 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2 and 18 recite that “the antigen binding domain comprises a VH region and/or a VL region.” Claims 1 and 14, from which claims 2 and 18 depend, require a VH region and a VL region. Thus, claims 2 and 18 further expands the scope of claims 1 and 14 and fail to further limit.
Claims 3 and 19 recite that the antigen binding domain comprises “a single VH domain, a single VL domain, or a protein domain specific for the antigen.” VH region or VL region is interpreted as synonymous to VH domain or VL domain. Claims 1 and 14, which ultimately from which claims 3 and 19, respectively, depend, require a VH region and a VL region. Moreover, an antigen binding domain comprising a VH and a VL region is a protein domain specific for an antigen. Thus, the recitation of a single VH domain, a single VL domain, or a protein domain specific for the antigen further expands the scope of claims 1 and 14 and fails to further limit.
Claims 5 and 20 recite that the binding molecules are engineered antigen binding proteins. Claims 1 and 14 recite a binding molecule comprising Fc mutations. Thus, claims 1 and 14, from which claim 5 and 20 depend, recite a particular engineered binding molecule and claims 5 and 20 further expand the scope and fail to further limit claims 1 and 14. Moreover, claims 1 and 14 are indefinite for reciting that the antigen binding domain is monovalent. If claims 1 and 14 are amended recite that the binding molecule is monovalent, then the recitation of a monovalent antibody in claims 5 and 20 would not further limit.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 13-20, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018) in view of Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013), and Attar et al. (WO 2020/148677 A1; Published: July 23, 2020).
Regarding the K248E and T437R mutations in claims 1, 14 and 15, Armstrong et al. teaches an engineered antibody comprising the K248E and T437R mutations; see claims 1, 3, and 4 for example. Regarding hexamerization in claim 1, Armstrong et al. teaches that mutations K248E and T437R facilitate hexamerization and such an IgG hexamer can greatly activate complement-dependent cytotoxicity (CDC); see Example 2 and paragraph 0467. Further, regarding claims 6 and 23, Armstrong et al. teaches that the K248E and T437R mutations mediate ADCC, ADCP, and CDC; see paragraphs 0191-0196.
Regarding monovalent binding proteins or antigen binding domains in claims 1, 2, 3, 5, 14, 15, 16, 19, and 20, Armstrong et al. teaches that the antigen binding site comprising a VH and a VL region may be in a Fab or scFv format and that the overall binding protein may be monovalent; see paragraph 0056-0057.
Regarding the lack of a core fucose of N297 in claims 4, 14, and 26, Armstrong et al. teaches that N297 of IgG1 and IgG3 is N-glycosylated and that removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc regions enhances the ADCC without altering antigen binding or CDC activity; see paragraph 0327. Armstrong et al. teaches methods of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides; see paragraph 0327. Regarding the percent fucose of claim 14, 15, and 17, Armstrong et al. teaches that the fucose content of a “low fucose” antibody having enhanced effector function would be less than 15%; see paragraphs 0331, 0333, and 0334.
Regarding claims 24-26, Armstrong et al. teaches polynucleotides encoding the Fc domain comprising the K248E and T437R mutations, vectors comprising the polynucleotides, and methods of producing the Fc domain.
Armstrong et al. does not teach the antigen binding domain comprising the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 334.
Nor does Amstrong et al. teach an antigen binding domain comprising the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 332.
Attar et al. teaches a CAR comprising an anti-GPRC5D scFv comprising SEQ ID NO: 75; see claim 8 for example. Attar et al. SEQ ID NO: 75 residues 1-125 is 100% identical to residues 1-125 of instant SEQ ID NO: 257 and Attar et al. SEQ ID NO: 75 residues 146-252 is 100% identical to residues 1-107 of instant SEQ ID NO: 259.
It would have been obvious to substitute the anti-TNFR antigen binding domain of the Fc modified antibody comprising the K248E and T437R mutations taught by Armstrong et al. with the anti-GPRC5D scFv antigen binding domain taught by Attar et al. since both Armstrong et al. and Attar et al. teach that TNFR and GPRC5D are appropriate target antigens for treating cancer; see claims 27-29 of Armstrong et al. and claim 39 of Attar et al. for example. One of ordinary skill in the art would have been motivated to produce an anti-GPRC5D antibody comprising the modified Fc region taught by Armstrong et al. for the enhanced ADCC, CDC, and ADCP against cancers expressing GPRC5D. One would have had a reasonable expectation of success using the modified Fc region in an anti-GPRC5D antibody because while Armstrong et al. claims an anti-TNFR antibody comprising the modified Fc region, Armstrong et al. teaches antibodies with other targets, for example, anti-CD40 and anti-GITR; see page 23.
Regarding monovalent binding proteins, Armstrong et al. teaches that the antibody produced may be monovalent and that the Fc region may comprise further modifications, including knob-in-hole modifications to generate CrossMAb antibodies; see paragraphs 0057 and 0370-0371. Given that Armstrong et al. teaches that binding molecule may be monovalent and Attar et al. teaches an scFv antigen binding domain, which is inherently monovalent as evidenced by Armstrong et al. paragraph 0056, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce a monovalent binding molecule. One would have been motivated to produce a monovalent binding molecule because Wang et al. teaches that monovalent antibodies demonstrate augmented ADCC and CDC; see page 4 left column. Further, Merchant et al. teaches a one-armed monovalent antibody generated by knob-in-hole mutations. Merchant et al. teaches that the monovalent antibody is purified to 95% of the main peak by size exclusion chromatography; see E2988.
Finally, regarding N297 afucosylation, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce the binding molecule having reduced N297 fucose content because Armstrong et al. teaches that the binding molecule comprising the K248E and T437R mutations are further engineered to have a fucose content of 0-15%. One would have been motivated to produce low fucose binding molecules because Armstrong et al. teaches that low fucose antibodies demonstrate enhanced ADCC.
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 application, as evidenced by the references.
Claims 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018) in view of Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013), and Attar et al. (WO 2020/148677 A1; Published: July 23, 2020) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
The teachings of Armstrong et al. in view of Wang et al., Merchant et al., and Attar et al. as related to claim(s) 1-6, 13-20, and 23-26, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Armstrong et al. teaches methods of generating afucosylated antibody including using the host cell CHO line EB66, the reference does not teach that this host cell is deficient in adding a fucose because it has decreased FUT8 activity.
Regarding claims 21 and 22, Shinkawa et al. teaches the hybridoma cell line YB2/0 which produces low fucose antibodies and has lower expression of FUT8; see Abstract.
It would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to produce the binding molecule or population of binding molecules having reduced core fucose at N297 using the YB2/0 cell line having reduced FUT8 activity because Armstrong et al. teaches using the YB2/0 cell line to produce antibodies with reduce N297 fucose content. One would have been motivated to use the YB2/0 because, as also taught in Armstrong et al., Shinkawa et al. teaches that antibodies produced by YB2/0 demonstrated 50-fold higher ADCC; see Abstract.
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 application, as evidenced by the references.
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 1-6, 13-20, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 14-16, and 18 of U.S. Patent No. 10,669,344 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018),Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013), and Attar et al. (WO 2020/148677 A1; Published: July 23, 2020).
Regarding the K248E and T437R mutations in instant claims 1, 14 and 15, issued claims 1, 3, 14, and 16 teach an engineered antibody or isolated Fc domain comprising the K248E and T437R mutations; see claims 1, 3, and 4 for example.
The issued claims do not teach hexamerization, monovalent binding molecules, afucosylation at N297, nor polynucleotides, vectors, and methods of producing the binding molecule.
Like the issued claims, Armstrong et al. teaches an engineered antibody comprising the K248E and T437R mutations; see claims 1, 3, and 4 for example. Regarding hexamerization in instant claim 1, Armstrong et al. teaches that mutations K248E and T437R facilitate hexamerization and such an IgG hexamer can greatly activate complement-dependent cytotoxicity (CDC); see Example 2 and paragraph 0467. Further, regarding instant claims 6 and 23, Armstrong et al. teaches that the K248E and T437R mutations mediate ADCC, ADCP, and CDC; see paragraphs 0191-0196.
Regarding monovalent binding proteins or antigen binding domains in instant claims 1, 2, 3, 5, 14, 15, 16, 19, and 20, Armstrong et al. teaches that the antigen binding site comprising a VH and a VL region may be in a Fab or scFv format and that the overall binding protein may be monovalent; see paragraph 0056-0057.
Regarding the lack of a core fucose of N297 in instant claims 4, 14, and 26, Armstrong et al. teaches that N297 of IgG1 and IgG3 is N-glycosylated and that removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc regions enhances the ADCC without altering antigen binding or CDC activity; see paragraph 0327. Armstrong et al. teaches methods of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides; see paragraph 0327. Regarding the percent fucose of instant claim 14, 15, and 17, Armstrong et al. teaches that the fucose content of a “low fucose” antibody having enhanced effector function would be less than 15%; see paragraphs 0331, 0333, and 0334.
Regarding instant claims 24-26, Armstrong et al. teaches polynucleotides encoding the Fc domain comprising the K248E and T437R mutations, vectors comprising the polynucleotides, and methods of producing the Fc domain.
Neither the issued claims nor Armstrong et al. teach the antigen binding domain comprising the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 334.
Nor does Amstrong et al. teach an antigen binding domain comprising the VH and VL regions, respectively, of:
Amino acids 1-125 of SEQ ID NO: 257 and amino acids 1-107 of SEQ ID NO: 259;
Amino acids 1-125 of SEQ ID NO: 291 and amino acids 1-107 of SEQ ID NO: 294; or
Amino acids 1-125 of SEQ ID NO: 327 and amino acids 1-113 of SEQ ID NO: 332.
Attar et al. teaches a CAR comprising an anti-GPRC5D scFv comprising SEQ ID NO: 75; see claim 8 for example. Attar et al. SEQ ID NO: 75 residues 1-125 is 100% identical to residues 1-125 of instant SEQ ID NO: 257 and Attar et al. SEQ ID NO: 75 residues 146-252 is 100% identical to residues 1-107 of instant SEQ ID NO: 259.
It would have been obvious to substitute the anti-TNFR antigen binding domain of the Fc modified antibody comprising the K248E and T437R mutations taught by the issues claims or Armstrong et al. with the anti-GPRC5D scFv antigen binding domain taught by Attar et al. since both Armstrong et al. and Attar et al. teach that TNFR and GPRC5D are appropriate target antigens for treating cancer; see claims 27-29 of Armstrong et al. and claim 39 of Attar et al. for example. One of ordinary skill in the art would have been motivated to produce an anti-GPRC5D antibody comprising the modified Fc region taught by the issued claims or Armstrong et al. for the enhanced ADCC, CDC, and ADCP against cancers expressing GPRC5D. One would have had a reasonable expectation of success using the modified Fc region in an anti-GPRC5D antibody because while Armstrong et al. claims an anti-TNFR antibody comprising the modified Fc region, Armstrong et al. teaches antibodies with other targets, for example, anti-CD40 and anti-GITR; see page 23.
Regarding monovalent binding proteins, Armstrong et al. teaches that the antibody produced may be monovalent and that the issued claims and Armstrong et al. teach that the Fc region may comprise further modifications, including knob-in-hole modifications to generate CrossMAb antibodies; see paragraphs 0057 and 0370-0371. Given that Armstrong et al. teaches that binding molecule may be monovalent and Attar et al. teaches an scFv antigen binding domain, which is inherently monovalent as evidenced by Armstrong et al. paragraph 0056, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce a monovalent binding molecule. One would have been motivated to produce a monovalent binding molecule because Wang et al. teaches that monovalent antibodies demonstrate augmented ADCC and CDC; see page 4 left column. Further, Merchant et al. teaches a one-armed monovalent antibody generated by knob-in-hole mutations. Merchant et al. teaches that the monovalent antibody is purified to 95% of the main peak by size exclusion chromatography; see E2988.
Finally, regarding N297 afucosylation, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce the binding molecule having reduced N297 fucose content because Armstrong et al. teaches that the binding molecule comprising the K248E and T437R mutations are further engineered to have a fucose content of 0-15%. One would have been motivated to produce low fucose binding molecules because Armstrong et al. teaches that low fucose antibodies demonstrate enhanced ADCC.
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 application, as evidenced by the references.
Claims 21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 14-16, and 18 of U.S. Patent No. 10,669,344 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013), and Attar et al. (WO 2020/148677 A1; Published: July 23, 2020) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
The teachings of U.S. Patent No. 10,669,344 B2 in view of Armstrong et al., Wang et al., Merchant et al., and Attar et al. as related to claim(s) 1-6, 13-20, and 23-26, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Armstrong et al. teaches methods of generating afucosylated antibody including using the host cell CHO line EB66, neither the issued claims, Armstrong et al., Wang et al., Merchant et al., nor Attar et al. teach that this host cell is deficient in adding a fucose because it has decreased FUT8 activity.
Regarding claims 21 and 22, Shinkawa et al. teaches the hybridoma cell line YB2/0 which produces low fucose antibodies and has lower expression of FUT8; see Abstract.
It would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to produce the binding molecule or population of binding molecules having reduced core fucose at N297 using the YB2/0 cell line having reduced FUT8 activity because Armstrong et al., which teaches the same K248E and T437R mutations as the issued claims, teaches using the YB2/0 cell line to produce antibodies with reduce N297 fucose content. One would have been motivated to use the YB2/0 because, as also taught in Armstrong et al., Shinkawa et al. teaches that antibodies produced by YB2/0 demonstrated 50-fold higher ADCC; see Abstract.
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 application, as evidenced by the references.
Claims 1-6, 13-20, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 6, 18, and 19 of U.S. Patent No. 12,077,592 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
Regarding instant claims 1, 14, and 15, issued claims 2, 3, and 6 teach a CAR comprising a scFv anti-GPRC5D antigen binding domain comprising SEQ ID NO: 75 with a VH and VL comprising issued SEQ ID NOs: 64 and 65. Issued SEQ ID NOs: 64 and 65 are 100% identical to instant SEQ ID NOs: 257 residues 1-125 and 259 residues 1-107. Issued SEQ ID NO: 75 residues 1-25 are 100% identical to instant SEQ ID NO: 257 residues 1-125 and issued SEQ ID NO: 75 residues 146-252 are 100% identical to SEQ ID NO: 259 residues 1-107. Issued claims 18 and 19 teach a CAR comprising SEQ ID NOs: 80, 83, and 84 which comprise an anti-GPRC5D antigen binding domain. Issued SEQ ID NO: 80 residues 147-252 are 100% identical to instant SEQ ID NO: 257 and issued SEQ ID NO: 80 residues 20-126 are 100% identical to instant SEQ ID NO: 259. Issued SEQ ID NO: 83 residues 1-125 are 100% identical to instant SEQ ID NO: 257 and issued SEQ ID NO: 83 residues 146-252 are 100% identical to instant SEQ ID NO: 259. Issued SEQ ID NO: 84 residues 128-252 are 100% identical to instant SEQ ID NO: 257 and issued SEQ ID NO: 84 residues 1-107 are 100% identical to instant SEQ ID NO: 259.
Claims 1-6, 13-20, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 5, 6, and 9 of U.S. Patent No. 12,071,466 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
Regarding instant claims 1, 14, and 15, issued claims 4, 5, 6, and 9 teach a CAR comprising a scFv anti-human kallikrein-2 antigen binding domain comprising a VH of SEQ ID NO: 142 and a VL of SEQ ID NO: 148. Issued SEQ ID NO: 142 is 100% identical to instant SEQ ID NO: 291 residues 1-125 and issued SEQ ID NO: 148 is 100% identical to SEQ ID NO: 294 residues 1-107. Issued SEQ ID NO: 175 residues 1-125 is 100% identical to instant SEQ ID NO: 291 residues 1-125 and issued SEQ ID NO: 175 residues 146-252 are 100% identical to instant SEQ ID NO: 294 residues 1-107.
Claims 1-6, 13-20, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, and 10-12 of U.S. Patent No. 12,077,585 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
Regarding instant claims 1, 14, and 15, issued claims 1 and 10 teach anti-kallikrein related peptidase 2 antigen binding domain comprising a VH and a VL of issued SEQ ID NOs: 162 and 163. Issued SEQ ID NO: 162 is 100% identical to instant SEQ ID NO: 291 residues 1-125 and issued SEQ ID NO: 163 is 100% identical to instant SEQ ID NO: 294 residues 1-107. Regarding monovalent binding molecules, issued claims 3, 4, 11, and 12 teach that the anti-kallikrein related peptidase 2 antigen binding domain may comprise scFv, a (scFv)2, a Fv, a Fab, or a F(ab′)2.
Claims 1-6, 13-20, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 11,827,708 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
Regarding instant claims 1, 14, and 15, issued claims 6 and 7 teach an anti-HLA-G antibody comprising the VH of SEQ ID NO: 50 which is 100% identical to instant SEQ ID NO: 327 residues 1-125 and the VL of SEQ ID NOs: 51 or 69 which is 100% identical to instant SEQ ID NO: 332 residues 1-113 or instant SEQ ID NO: 334 residues 1-113. Issued claim 8 teaches that the anti-HLA-G comprises SEQ ID NO: 249. Issued SEQ ID NO: 249 residues 1-113 are 100% identical to instant SEQ ID NO: 332 residues 1-113 and issued SEQ ID NO: 249 residues 134-258 are 100% identical to instant SEQ ID NO: 327 residues 1-125.
Claims 1-6, 13-20, and 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 and 20-22 of copending Application No. 18/262,980 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1, 14, and 15, copending claims 17 and 20-22 teach an immunoconjugate comprising an antigen binding domain that is a scFv, a (scFv)2, a Fv, a Fab, a F(ab')2, a Fd, a dAb or a VHH and comprises a VH of SEQ ID NO: 162 and a VL of SEQ ID NO: 163. Copending SEQ ID NO: 162 is 100% identical to instant SEQ ID NO: 291 residues 1-125 and copending SEQ ID NO: 163 is 100% identical to instant SEQ ID NO: 294 residues 1-107
Claims 1-6, 13-20, and 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 6-8, and 10 of copending Application No. 18/832,652 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013).
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1, 14, and 15, copending claims 4, 6-8, and 10 teach an immunoconjugate comprising an antigen binding domain that is a Fab and comprises a VH of SEQ ID NO: 162 and a VL of SEQ ID NO: 163. Copending SEQ ID NO: 162 is 100% identical to instant SEQ ID NO: 291 residues 1-125 and copending SEQ ID NO: 163 is 100% identical to instant SEQ ID NO: 294 residues 1-107
The following analysis applies to the nonstatutory double patenting rejections over the issued claims of U.S. Patent Nos. 12,077,592 B2; 12,071,466 B2; 12,077,585 B2; or 11,827,708 B2 or the copending claims of Application Nos. 18/262,980 or 18/832,652.
The issued claims of U.S. Patent Nos. 12,077,592 B2; 12,071,466 B2; 12,077,585 B2; or 11,827,708 B2 or the copending claims of Application Nos. 18/262,980 or 18/832,652 do not teach the Fc domain comprising the K248E and T437R mutations, afucosylation of N297, nor that the binding molecule is monovalent.
Regarding the K248E and T437R mutations in instant claims 1, 14 and 15, Armstrong et al. teaches an engineered antibody comprising the K248E and T437R mutations; see claims 1, 3, and 4 for example. Regarding hexamerization in instant claim 1, Armstrong et al. teaches that mutations K248E and T437R facilitate hexamerization and such an IgG hexamer can greatly activate complement-dependent cytotoxicity (CDC); see Example 2 and paragraph 0467. Further, regarding instant claims 6 and 23, Armstrong et al. teaches that the K248E and T437R mutations mediate ADCC, ADCP, and CDC; see paragraphs 0191-0196.
Regarding monovalent binding proteins or antigen binding domains in instant claims 1, 2, 3, 5, 14, 15, 16, 19, and 20, Armstrong et al. teaches that the antigen binding site comprising a VH and a VL region may be in a Fab or scFv format and that the overall binding protein may be monovalent; see paragraph 0056-0057.
Regarding the lack of a core fucose of N297 in instant claims 4, 14, and 26, Armstrong et al. teaches that N297 of IgG1 and IgG3 is N-glycosylated and that removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc regions enhances the ADCC without altering antigen binding or CDC activity; see paragraph 0327. Armstrong et al. teaches methods of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides; see paragraph 0327. Regarding the percent fucose of instant claim 14, 15, and 17, Armstrong et al. teaches that the fucose content of a “low fucose” antibody having enhanced effector function would be less than 15%; see paragraphs 0331, 0333, and 0334.
Regarding instant claims 24-26, Armstrong et al. teaches polynucleotides encoding the Fc domain comprising the K248E and T437R mutations, vectors comprising the polynucleotides, and methods of producing the Fc domain.
It would have been obvious to substitute the anti-TNFR antigen binding domain of the Fc modified antibody comprising the K248E and T437R mutations taught by Armstrong et al. with one of the anti-GPRC5D, anti-HLA-G, or anti-kallikrein related peptidase 2 antigen binding domains taught by the issued or copending claims since TNFR and GPRC5D, HLA-G, or kallikrein related peptidase 2 are appropriate target antigens for treating cancer; see claims 27-29 of Armstrong et al. for example. One of ordinary skill in the art would have been motivated to produce an anti-GPRC5D, anti-HLA-G, or anti-kallikrein related peptidase 2 antibody comprising the modified Fc region taught by Armstrong et al. for the enhanced ADCC, CDC, and ADCP against cancers expressing GPRC5D, HLA-G, or kallikrein related peptidase 2. One would have had a reasonable expectation of success using the modified Fc region in an anti-GPRC5D, anti-HLA-G, or anti-kallikrein related peptidase 2 antibody because while Armstrong et al. claims an anti-TNFR antibody comprising the modified Fc region, Armstrong et al. teaches antibodies with other targets, for example, anti-CD40 and anti-GITR; see page 23.
Regarding monovalent binding proteins, Armstrong et al. teaches that the antibody produced may be monovalent and that the Fc region may comprise further modifications, including knob-in-hole modifications to generate CrossMAb antibodies; see paragraphs 0057 and 0370-0371. Given that Armstrong et al. teaches that binding molecule may be monovalent, including an scFv antigen binding domain, which is inherently monovalent as evidenced by Armstrong et al. paragraph 0056, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce a monovalent binding molecule. One would have been motivated to produce a monovalent binding molecule because Wang et al. teaches that monovalent antibodies demonstrate augmented ADCC and CDC; see page 4 left column. Further, Merchant et al. teaches a one-armed monovalent antibody generated by knob-in-hole mutations. And, Merchant et al. teaches that the monovalent antibody is purified to 95% of the main peak by size exclusion chromatography; see E2988.
Finally, regarding N297 afucosylation, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce the binding molecule having reduced N297 fucose content because Armstrong et al. teaches that the binding molecule comprising the K248E and T437R mutations are further engineered to have a fucose content of 0-15%. One would have been motivated to produce low fucose binding molecules because Armstrong et al. teaches that low fucose antibodies demonstrate enhanced ADCC.
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 application, as evidenced by the references.
Claims 21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 6, 18, and 19 of U.S. Patent No. 12,077,592 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018),Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
Claims 21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 5, 6, and 9 of U.S. Patent No. 12,071,466 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
Claims 21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, and 10-12 of U.S. Patent No. 12,077,585 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
Claims 21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 11,827,708 B2 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
Claims 21 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 and 20-22 of copending Application No. 18/262,980 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
This is a provisional nonstatutory double patenting rejection.
Claims 21 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 6-8, and 10 of copending Application No. 18/832,652 in view of Armstrong et al. (US 2018/0044427 A1; Published: February 15, 2018), Wang et al. (mAbs. 12(1): e1690959; Published: December 12, 2019), and Merchant et al. (PNAS. 110(32): E2987-E2996; Published Online: July 23, 2013) as applied to claim(s) 1-6, 13-20, and 23-26 above, and further in view of Shinkawa et al. (Journal of Biological Chemistry. 278(5): 3466-3473; Published: January 31, 2003).
This is a provisional nonstatutory double patenting rejection.
The following analysis applies to the nonstatutory double patenting rejections over the issued claims of U.S. Patent Nos. 12,077,592 B2; 12,071,466 B2; 12,077,585 B2; or 11,827,708 B2 or the copending claims of Application Nos. 18/262,980 or 18/832,652.
The teachings of U.S. Patent Nos. 12,077,592 B2; 12,071,466 B2; 12,077,585 B2; or 11,827,708 B2 or Application Nos. 18/262,980; 18/397,711; or 18/832,652 in view of Armstrong et al., Wang et al., and Merchant et al., as related to claim(s) 1-6, 13-20, and 23-26, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither the issued claims of U.S. Patent Nos. 12,077,592 B2; 12,071,466 B2; 12,077,585 B2; or 11,827,708 B2 nor the copending claims of Application Nos. 18/262,980 or 18/832,652, nor Armstrong et al, Wang et al., nor Merchant et al. teach producing a afucosylated binding protein in a host cell with reduced FUT8 activity.
Regarding claims 21 and 22, Shinkawa et al. teaches the hybridoma cell line YB2/0 which produces low fucose antibodies and has lower expression of FUT8; see Abstract.
It would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to produce the binding molecule or population of binding molecules having reduced core fucose at N297 using the YB2/0 cell line having reduced FUT8 activity because Armstrong et al. teaches using the YB2/0 cell line to produce antibodies with reduce N297 fucose content. One would have been motivated to use the YB2/0 because, as also taught in Armstrong et al., Shinkawa et al. teaches that antibodies produced by YB2/0 demonstrated 50-fold higher ADCC; see Abstract.
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 application, as evidenced by the references.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571)272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
Prosecution Insights