DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/IB2021/000665, filed 9/30/2021; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 63/227241, filed 7/29/2021, and 63/085560, filed 9/30/2020.
Information Disclosure Statement
The information disclosure statement filed 1/17/2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because it fails to provide the content required under 37 C.F.R. 1.98; for example, it does not provide a space for examiner's initials. It has been placed in the application file, properly, as a “transmittal letter,” but the information referred to therein has not been considered as to the merits, unless the reference is also listed on a proper IDS. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Status of Claims
Claims 1-9, 11, 13, 15, 17, 20-26, 28-38, 40, 58-60 are pending and are being examined on the merits.
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 #1- This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
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) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency #2- This application contains a “Sequence Listing as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)), but fails to comply with the requirements of 37 CFR 1.821 - 1.825 because a copy of the "Sequence Listing" in computer readable form (CRF) has not been submitted as required by 37 CFR 1.821(e)(1)(i) or 1.821(e)(2)(i) as indicated in item 2) above.
Required response - Applicant must provide:
A new CRF of the “Sequence Listing” in accordance with 37 CFR 1.821(e)(1)(i) or 1.821(e)(2)(i) and
A statement that the content of the CRF is identical of the “Sequence Listing” part of the disclosure, submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)), as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
Specification Objections
The disclosure is objected to because of the following informalities: The disclosure recites SEQ ID NOs without having a computerized sequence listing in the application; for example pg. 5, para. 0019. Appropriate correction is required.
Claim Objections
Claims 1, 5, 7, 25 and 28-30 are objected to because of the following informalities: The claims recite SEQ ID NOs without having a computerized sequence listing in the application. Appropriate correction is required.
Claim 40 objected to because of the following informalities: Claim 40(c) begins with a copyright symbol (i.e., ©). This is believed to be a typo. 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.
Claims 1-9, 11, 13, 15, 17, 20-26, 28-38, 40 and 58-60 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.
The term “about” in claims 22, 24, 29-33, 38 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, the metes and bounds of the claim are unclear when specific parameters are expressed as claim limitations, but lack specificity regarding the specific range encompassed by the parameters. As the metes and bounds are unclear, the artisan cannot know what constitutes infringement of the claim.
Regarding claims 8 and 25; where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “kappa 2” in claims 8 and 25 is used by the claim to mean “a human kappa light chain,” while the accepted meaning is “kappa.” The term is indefinite because the specification does not clearly redefine the term. Specifically, it is unclear if “kappa 2” is a different light chain, comprising a different amino acid sequence, from the kappa light chain of an IgG molecule. If the term is intended to signify an IgG kappa light chain that is structurally different than the genus of IgG kappa light chains of the art, then “kappa 2” should be clearly defined, and the required sequence structure to which the claims are limited should also be defined. If the term is generic to IgG kappa light chains, then the term should be “kappa”, and not “kappa 2”.
Claims 38 and 40 recite “wherein a subject for treatment comprises, or treatment efficacy is indicated based on, one of the following, as compared to a control or an untreated patient, (a) an increase in serum IFNγ of at least about 10%...”. It is unclear if the claims are drawn to selecting a patient for treatment, “wherein a subject for treatment comprises”, or if the claim is drawn to assessments for treatment efficacy, “treatment efficacy is indicated based on”. That is, it is unclear if, “wherein a subject for treatment comprises…an increased IFNγ level”, means the increased IFNγ level is a diagnostic for selecting a patient suitable for treatment; if so, is their increased IFNγ level not a result of already being treated? If the claim is intended to recite only the after-treatment effects in the patient, examiner suggests amended the claim to recite “wherein the subject of the treatment comprises…”.
Claims 1 and 29 recite wherein the anti-PVRIG antibody comprise the CDRs of the heavy chain and light chain of SEQ ID NOs: 4 and 9, respectively. However, it is not clear how the CDRs are defined as there are various numbering schemes for defining which residues constitute each CDR of an antibody heavy or light chain; examples of different numbering schemes include IMGT, Chothia, Kabat, among others. The instant specifications (pg. 32, para. 0163) teach that the LCDR1 encompasses amino acid residues 24-34 according to Kabat numbering, but LCDR1 encompasses amino acid residues 26-32 according to Chothia. As the minimum number of residues of the LCDR1 for Chothia numbering (i.e., 7 residues) is less than that of Kabat (i.e., 11 residues), it is unclear what the metes and bounds of the required CDRs of the antibody are. For example, if an artisan has an antibody that has the same amino acid residues at positions 26-32, but differs in amino acid residues at positions 24-25 and 33-34; is the antibody within the scope of the claim or not? As it is unclear exactly which residues constitute, for example, the “vlCDR1 from the light chain of SEQ ID NO: 9”, the metes and bounds of the claimed structure are unclear, and the claim is indefinite. Claims 2-9, 11, 13, 15, 17, 20-24, 26, 29, 31-38, 40, 58-60 depend from claim 1 but fail to rectify the indefiniteness.
Claims 1, 25, and 28-30 recites CHA.7.518.1.H4(S241) and a SEQ ID NO, where it is unclear which is the reference. Specifically, claim 1 recites wherein the anti-PVRIG antibody comprise a heavy chain of CHA.7.518.1.H4(S241) (SEQ ID NO: 4) and a light chain of CHA.7.518.1.H4(S241) (SEQ ID NO: 9). It is unclear if the antibody name is identical to the sequences. That is, if an antibody has SEQ ID NOs: 4 and 9, is it always CHA.7.518.1.H4(S241)? Does it need to have a particular heavy or light chain constant region? If an antibody has the VH and VL of SEQ ID NOs: 4 and 9, respectively, but does not comprise a CH1-hinge-CH2-CH3 region with a S241P mutation (see claims 5-6; specs., pg. 5, para. 0017), would it still be the CHA.7.518.1.H4(S241) antibody; or is the CHA.7.518.1.H4(S241) antibody a more limited embodiment of an antibody comprising the VH and VL of SEQ ID NOs: 4 and 9? If so, which one is being claimed? As it is unclear if CHA.7.518.1.H4(S241) and any antibody with SEQ ID NOs: 4 and 9 are identical and synonymous, or are two (or more) different species of a genus of antibodies comprising SEQ ID NOs: 4 and 9, it is unclear what antibody is required in the claim, and what the metes and bounds of the claim are; thus the claims 1, 25 and 28-30 are indefinite. Claims 2-9, 11, 13, 15, 17, 20-24, 26, 29, 31-38, 40, 58-60 depend from claim 1 but fail to rectify the indefiniteness.
Claim Rejections - 35 USC § 103
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.
Claims 1-9, 11, 13, 15, 17, 20-26, 28-32, 38, 40 and 58-60 are rejected under 35 U.S.C. 103 as being obvious over Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020).
The applied reference has a common inventor with the instant application; specifically US 20190010246 lists Eran Ophir as an inventor. However, based upon the earlier publication date of the reference, whereby it was published > 1 year before the earliest effective filing date of the instant application, it constitutes prior art under 35 U.S.C. 102(a)(1) and (a)(2).
Liang et al. teaches triple combination therapies with anti-TIGIT antibodies, anti-PVRIG antibodies, and checkpoint inhibitors, including anti-PD-1 or anti-PD-L1 antibodies (abstract).
Regarding the anti-PVRIG antibodies, Liang teaches the anti-PVRIG antibody is CHA.7.518.H4(S241P), (pg. 1, para. 0010; pg. 70, claim 61). Liang teaches CHA.7.518.H4(S241P) comprises the VH, VL and 6 CDR amino acid sequences according to Fig. 5 (pg. 29, para. 0317); whereby the VH is SEQ ID NO: 1019 and the VL is SEQ ID NO: 1024 (see Fig. 5A). The VH and VL of Liang SEQ ID NO: 1019 and 1024 are 100% identical to instant SEQ ID NO: 4 and 9, respectively, as shown in instant Figure 3 (see drawings). Thus, the CHA.7.518.H4(S241P) anti-PVRIG antibody of Liang is the same as that of instant claim 1.
Regarding the anti-TIGIT antibodies, the instant specifications describe the BMS-986207 of instant claim 1 as mAb 22G2 in previous disclosures (instant specs., pg. 45, para. 0215); comprising the VH CDRs of SEQ ID NOs: 50-52 and the VL CDRs of SEQ ID NOs: 53-55 (para. 0216). Liang also teaches mAb 22G2; comprising the VH of Liang SEQ ID NO: 136 and the VL of SEQ ID NO: 141 (see Liam Fig. 3M for hIgG4 22G2). The VH of Liang SEQ ID NO: 136 comprises the VH CDRs of instant SEQ ID NOs: 50-52 with 100% identity, and the VL of Liang SEQ ID NO: 141 comprises the VL CDRs of instant SEQ ID NOs: 53-55 with 100% identity. Thus, the examiner asserts that the mAb 22G2 of Liang is the same as instant antibody BMS-986207. Further, Liang teaches that in some embodiments, the anti-TIGIT antibody is 22G2, and that “specifically, the anti-TIGIT antibody 22G2 can be combined with CHA.7.518.1.H4(S241P)”, (pg. 24, para. 0254).
Regarding the anti-PD-1 antibodies, Liang teaches the anti-PD-1 antibody is chosen from at least one of pembrolizumab, cemiplimab and nivolumab (pg. 4, para. 0040; pg. 70, claim 62).
Thus, Liang teaches a method of treating cancer in a patient comprising administering a triple combination therapy comprising an anti-TIGIT antibody, an anti-PVRIG antibody, and an anti-PD-1 antibody (pg. 70, claim 59c); whereby the anti-PVRIG antibody is CHA.7.518.1.H4(S241P), whereby the anti-PD-1 antibody is nivolumab (pg. 70, claims 61-62), and whereby the anti-TIGIT antibody is 22G2, which is the same as BMS-986207 (pg. 24, para. 0254). Thus, the methods taught by Liang make obvious the triple combination method of instant claim 1. Further, Liang teaches antibodies may be formulated into pharmaceutical compositions comprising a carrier, which may be any of a number of standard pharmaceutical carriers such as sterile PBS (pg. 37, para. 0438). However, Liang does not teach the formulation for the anti-PVRIG antibody of instant claim 1(b)-(e).
Blake-Haskins teaches pharmaceutical formulation of, for example, a monoclonal antibody, whereby the formulations include a buffering agent and a tonicity agent (abstract). Blake-Haskins teaches the formulation comprises a buffering agent, a tonicity agent, a stabilizer and a surfactant. Blake-Haskins teaches the buffering agent provides a pH of about 5.0 to about 7.0, and that buffering agent may be histidine (col. 9, lines 11-23). The tonicity agent is sodium chloride (i.e., NaCl), whereby the NaCl concentration is about 70 to 170 mM (col. 9, lines 31-37). The stabilizer is arginine, with a concentration of 20 to 30 mM arginine (col. 9, lines 50-64). The surfactant is polysorbate 80, with a concentration of 0.01% weight/volume (col. 10, lines 1-13). Thus, Blake-Haskins claims one such formulation embodiment as comprising: 200 mg/mL of antigen binding protein, 5-15 mM of histidine providing a pH of 6.0, 115 mM NaCl, 20-30 mM of arginine, and 0.005 to 0.015% w/v of polysorbate 80 (col. 57, claim 1). Blake-Haskins teaches the problem with high concentration antibody formulations is the high viscosity of the formulation, which results in clinical challenges, such as high injection forces and increased pain at the injection site when administering subcutaneously (col. 29, lines 49-58). Regarding the NaCl, Blake-Haskins teaches the NaCl may be about 70-170 mM. Blake-Haskins provides Example 7 (col. 30), and Figure 18, to highlight the dependence of viscosity on protein concentration and sodium content (col. 31, lines 60-61). Blake-Haskins Fig. 18 displays a comparison of buffers comprising high concentrations of antibody, with or without 150 mM NaCl; whereby the inclusion of 150 mM NaCl decreases the viscosity from ~65.00 cP to ~10.00 cP (see Fig. 18). Thus, Blake-Haskins highlights the role of NaCl is to reduce the viscosity of formulations comprising high concentration antibody (col. 32, lines 4-6). Thus, Blake-Haskins teaches the range of NaCl may be from 70-170 mM, and the chosen range may be dependent on the desired viscosity of the formulation.
It would have been obvious to one of skill in the art to modify the formulation of Blake-Haskins to comprise 70-100 mM NaCl, with motivation and reasonable expectation for success provided by Blake-Haskins teachings that the concentration of NaCl may be modified based on the desired final viscosity. Given that the instant anti-PVRIG antibody may be formulated with one or both of the anti-TIGIT antibody or the PD-1 antibody (see instant claim 2), which would result in a higher concentration of total antigen-binding protein per formulation, the artisan would be motivated to modify the formulation appropriately to reduce the viscosity, and would do so by modifying the concentration of NaCl, as taught by Blake-Haskins. MPEP section 2144.05(II)(A) supports the routine optimization of concentrations by a skilled artisan as obvious over the prior art. Thus, it is within the scope of formulations taught by Blake-Haskins to have an embodiment formulation comprising 70-100 mM NaCl, with 5-15 mM of histidine providing a pH of 6.0, 20-30 mM of arginine (which may be L-arginine, see col. 60, claim 23), and 0.005 to 0.015% w/v of polysorbate 80 (col. 57, claim 1). Thus, the formulations taught by Blake-Haskins make obvious the formulation of instant claim 1(b)-(e).
It would have been obvious to one of skill in the art to modify the triple combination therapy of Liang et al., comprising administering an anti-TIGIT antibody (BMS-986207, aka. 22G2), an anti-PVRIG antibody (CHA.7.518.1.H4(S241P)), and an anti-PD-1 antibody (nivolumab), whereby the anti-PVRIG antibody is formulated in the buffer of Blake-Haskins et al. One would have been motivated to do so in order to reduce the viscosity of the anti-PVRIG antibody for administration, including wherein the anti-PVRIG antibody is co-formulated with the other antibodies of the therapy for simultaneous administration, such that the reduced viscosity reduces the injection force and pain at the injection site, as taught by Blake-Haskins. There would have been a reasonable expectation for success given that the formulations of Blake-Haskins reduced the viscosity of high concentration antibody compositions. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 1, 3-4, 7, 9, 11, 13, 15 and 17. The combination of the triple combination therapy of Liang et al., whereby the anti-PVRIG antibody is formulated according to Blake-Haskins et al. makes obvious the method of claim 1, as described above. Given that saline is a NaCl solution (154 mM), and Blake-Haskins teaches modifying the NaCl concentration to alter the viscosity, it is encompassed within the teachings of Blake-Haskins to dilute the anti-PVRIG antibody composition in saline, so as to alter the final NaCl concentration. Thus, the combination of Liang and Blake-Haskins makes obvious instant claims 3-4. Further, the anti-PVRIG antibody is CHA.7.518.1.H4(S241P), and therefore comprises the VH of instant SEQ ID NO: 4 and the VL of instant SEQ ID NO: 9, as described above; therefore, claim 7 is made obvious. Blake-Haskins teaches a formulation comprising 15 mM histidine, 70 mM NaCl, 30 mM L-arginine, and 0.005%-0.015% w/v polysorbate 80, whereby the pH is 6.0 ±0.5; and thus makes obvious instant claims 9, 11, 13, 15 and 17, respectively.
Regarding claims 29-30, while the claims only differ from claim 1 by recitation of a “narrower range” of concentrations of the ingredients of the formulation; however, the claims list the exact concentrations as “about”. No definition of about is recited in the instant specifications. Further, the ability of the skilled artisan to modify the formulation as taught by Blake-Haskins across varying ranges in order to optimize the formulation by methods routine in the art are described above (see MPEP section 2144.05). Nonetheless, Blake-Haskins teaches the histidine concentration may be 25 mM (col. 9, lines 3-6). Blake-Haskins teaches the NaCl concentration is “about” 70-170 mM, whereby “about” encompasses ±20% variation (col. 3, lines 29-31); therefore Blake-Haskins encompasses 60 mM NaCl. Blake-Haskins teaches the polysorbate 80 is at a concentration of 0.01% w/v and the pH is 6.0 ±0.5. Regarding the arginine, Blake-Haskins teaches modifying the levels of arginine, including using 0, 25 and 50 mM arginine, to measure its effects on stability of the composition over time (col. 19, lines 34-36; Fig. 13). Blake-Haskins teaches that Formulation 5 (including histidine/NaCl/arginine) had the lowest rate of aggregation over 3 months, compared to formulations without arginine (col. 18, lines 41-45, Fig. 4). Blake-Haskins concluded “the aggregation rate was shown to increase with antibody concentration, but was inhibited by the use of 25 mM arginine,” (col. 22, lines 31-34). Thus, Blake-Haskins establishes that arginine is the result effective variable for mediating stability of the antibody formulations over time. MPEP section 2144.05(II) discusses routine optimization, and that differences in concentration will not support patentability unless there is evidence indicating such concentration is critical. Further, that a particular parameter must first be recognized as a result-effective variable before determination of the optimum ranges might be characterized as routine experimentation under the “obvious to try” rationale. Here, Blake-Haskins teaches that arginine is a “stabilizer” to the formulation, to prevent aggregation over time, and that increasing the concentration of arginine decreased the rates of aggregation. Blake-Haskins teaches using increasing concentrations, i.e., 25 or 50 mM arginine, for improving stability over time; therefore it would be obvious for a skilled artisan to try higher levels of arginine in order to increase formulation stability. In the manner of routine optimization, based on the teachings of Blake-Haskins, the artisan would arrive at 100 mM arginine concentration in the formulation. As Blake-Haskins teaches overlapping ranges of each of the necessary elements for formulating high concentration antibodies with long term storage stability (i.e. of claim 1), and it would be obvious for the skilled artisan to optimize and extend the concentration of arginine to 100 mM based on the teachings of Blake-Haskins, claims 29-30 are made obvious.
Regarding claim 2, Liang teaches the antibodies may be administered simultaneously or sequentially (col. 70, claims 67-68), and thus makes obvious instant claim 2.
Regarding claims 5-6, 8, 25-26 and 28 Liang teaches Fig. 1 depicts the amino acid sequences of the constant domains of human IgG4 with a hinge variant that finds particular use in the present invention, and the constant domains of the kappa light chains (pg. 7, para. 0108). Figure 1B shows the amino acid sequence of human IgG4 with a S241P hinge mutation, of SEQ ID NO: 7; and the amino acid sequence of human kappa light chain, of SEQ ID NO: 8. Liang Figure 5 shows the sequence of CHA.7.518.1.H4(S241P) comprises the IgG4 (S241P) constant region and the kappa light chain constant region. The full length HC and LC of Liang Figure 5 is identical to that of instant Figure 3; comprising the identical HC CH1-hinge-CH2-CH3 domain of instant SEQ ID NO: 56 (vs. Liang SEQ ID NO: 7), and the identical LC kappa domain (vs. Liang SEQ ID NO: 8). Thus, Liang teaches the anti-PVRIG antibody comprises the HC of instant claims 5-6 and the LC of instant claim 8. Therefore, the combination of Liang and Blake-Haskins makes obvious instant claims 5-6 and 8; as well as claims 25, 26 (wherein the hinge comprises the S241P mutation; see Liang pg. 17, para. 0195), and claim 28 (Liang Fig. 5A is identical to instant Fig. 3, comprising SEQ ID NOs: 8 and 13).
Regarding claims 20, 24 and 31-32. Liang teaches the anti-tumor responses to triple combination antibody treatments of a CT26 tumor model (pg. 58, Example 4) whereby the anti-PVRIG antibody may be administered at 10 mg/kg, the anti-TIGIT antibody at 18 mg/kg, and the anti-PD-L1 antibody at 5 mg/kg (pg. 58, para. 0816). Given that the skilled artisan, knowing the amount of antibody they want to administer to a subject, and that the subjects may vary in weight (kg), can modify the formulations comprising the antibodies to find an optimal concentration (mg/mL) suitable for administering the intended doses. See MPEP section 2144.05 describing routine optimization of concentrations across a range. Therefore, the combination of Liang and Blake-Haskins makes obvious administering 10 mg/kg of the anti-PVRIG antibody of instant claims 31-32; and also encompasses modifying the formulations of said anti-PVRIG to be 10 to 40 mg/mL, of claim 20, or 20 mg/mL of claim 24. Therefore claims 20, 24 and 31-32 are made obvious.
Regarding claims 21-23. The combination and formulation of instant claim 1 are made obvious by the combination of Liang and Blake-Haskins. As the combination recites the limitations of instant claim 1, the formulation comprises the inherent properties of being stable at 2-8°C; at 20-25°C or at 35-40°C for 1 or more weeks. Thus, claims 21-23 are made obvious.
Regarding claims 38, 40 and 58-60; Liang teaches the assessment of treatment, whereby the combination of antibodies are administered to patients with cancer and the efficacy is assessed (pg. 50, paras. 0712-0713). Liang teaches the assessments may be done both in vitro and in vivo assays and include assessing IFN-γ production by T cells or other immune cells (pg. 50, paras. 0713 and 0717). Liang teaches using a Mixed Lymphocyte Reaction (MLR) assay to measure increased immunostimulatory activity (pg. 51, para. 0724); and that in one embodiment the increased T cell activation includes increased cytokine production, including increases in IFN-γ (pg. 52, para. 0751). Thus, Liang teaches measuring IFN-γ production from circulating cells from peripheral blood (i.e., instant claim 59). Liang teaches that appropriate increases in activity or response are increases of at least 20% over the signal in either a reference sample or in control samples, whereby the specific increases in IFN-γ are measured; and whereby increases of at least one-, two-, three-, four- or five-fold, as compared to reference or control samples, show efficacy (pg. 53, paras. 0755-0756). Thus, as Liang teaches measuring IFN-γ production from circulating lymphocytes in peripheral blood, the combination of Liang and Blake-Haskins makes obvious instant claims 58-59. Further, as Liang teaches INF-γ increases of 20-99%, or 2- to 5-fold, are indicative of treatment efficacy, claims 38 and 40 are made obvious. Further, Liang teaches the cancer to be treated may be prostate cancer (pg. 70, claim 69), and thus makes obvious instant claim 60.
Claims 20, 24 and 31-37 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020) as applied to claims 1-9, 11, 13, 15, 17, 20-26, 28-32, 38, 40 and 58-60 above, and further in view of Maurer et al., (from IDS, Cite No. A123; WO 2016106302; published 6/30/2016).
The reasons why claims 1-9, 11, 13, 15, 17, 20-26, 28-32, 38, 40 and 58-60 are made obvious over the combination of Liang and Blake-Haskins are described above. Liang et al. teaches “specifically, the anti-TIGIT antibody 22G2 (from WO 2016/106302) can be combined with CHA.7.518.1.H4(S241P),” as described above, (see Liang, para. 0249, pg. 23, col. 1 bottom – col. 2 top). However, Liang does not teach all the limitations of dosing and administering the antibody combinations as cited in the instant claims (i.e., re. claims 33-37).
Maurer et al. (which is the WO 2016/106302 reference from Liang et al.) teaches antibodies that bind to TIGIT (title), as well as the 22G2 antibody (pg. 6, para. 0030; pg. 121, claim 1). Maurer also teaches administering the TIGIT antibody with additional antibodies, including an anti-PD-1 antibody (pg. 125, claim 30). Regarding compositions, Maurer teaches pharmaceutical compositions containing anti-TIGIT antibodies, whereby such compositions may include one or a combination of (e.g., two or more different) antibodies (pg. 71, para. 00252). Maurer teaches the antibody may be formulated at a concentration of 1-300 mg/mL (pg. 71, para. 00253). Regarding dosing and administration, Maurer teaches the antibody may be administered at dosage ranges from about 0.0001 to 100 mg/kg; and that an exemplary treatment regime entails administration once per week or once every four weeks (pg. 74, para. 00266). Further, Maurer teaches in some methods two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated (pg. 75, para. 00267).
It would have been obvious to one of skill in the art to modify the formulations, dosages and administration regime of the triple combination antibody therapy of the combination of Liang et al. and Blake-Haskins et al. to various ranges following the guidance of Maurer et al. One would be motivated to do so given that proper dosing and administration regimes would improve the therapeutic efficacy of the treatment for the subject. There would have been a reasonable expectation for success given that antibodies, including combinations of different antibodies, may be formulated and administered across a range of concentrations and across a range of administration regimes, as taught by Maurer et al. See MPEP section 2144.05 describing routine optimization of concentrations across a range. Thus selecting a specific embodiment from the varying concentrations, doses and administration regimes were prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 20, 24 and 31-37; Maurer teaches the antibody (or each antibody of the combination) may be formulated at a concentration of 1-300 mg/mL, and thus makes obvious instant claims 20 and 24. Maurer teaches each antibody of the combination may be administered at a dose range from about 0.0001 to 100 mg/kg; and thus makes obvious instant claims 31-32. It is obvious for a skilled artisan to adapt the dosing, encompassing the range of 0.0001 to 100 mg/kg, to result in administering a single dose of 480 mg of antibody to a subject; therefore the combination of Liang, Blake-Haskins and Maurer make obvious instant claims 33 and 36. Maurer teaches an administration regime that includes administering the antibody every 4 weeks, and thus makes obvious instant claims 34-35 and 37.
Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020) as applied to claims 1-9, 11, 13, 15, 17, 20-26, 28-32, 38, 40 and 58-60 above, and further in view of Liu et al., (US 2004/0197324; published 10/7/2004).
The examiner believes that claims 29-30 are made obvious over the methods of Liang and the formulations of Blake-Haskins, as described above. However, to the extent that applicant may argue that Blake-Haskins does not explicitly teach using “100 mM L-arginine” in the formulation of the anti-PVRIG antibody, the following additional rejection is pertinent to that limitation, recited in claims 29-30.
Liu et al. teaches highly concentrated antibody and protein formulations with reduced viscosity that are stable and are particularly suitable for subcutaneous administration (abstract). Liu teaches “applicants have discovered that Arginine, specifically Arginine-HCL is particularly suited for highly concentrated liquid protein or antibody formulations,” (pg. 1, para. 0008). Liu teaches the present invention concerns highly concentrated antibody formulations with 10-100 mM histidine, 50-200 mM arginine-HCL, 0.01%-0.1% polysorbate, with a pH of 5.5-7.0; alternatively, the concentration of arginine-HCL ranges from 100-200 mM, or 150-200 mM or 180-200 mM (pg. 1, para. 12; pg. 39, claims 8-9). Liu teaches inclusion of varying amounts of arginine (shaded symbols) increased the stability of formulations over storage times (months) compared to formulations with no arginine (clear, non-shaded symbols); see Figures 8-9.
It would have been obvious to one of skill in the art to modify the formulations of Liang and Blake-Haskins to comprises 100 mM L-arginine. One would have been motivated to do so given that arginine increases stability of antibody formulations over time as taught by Blake-Haskins and as taught by Liu et al. There would have been a reasonable expectation for success given that Blake-Haskins teaches 25 and 50 mM arginine improved stability over time compared to 0 mM arginine, and that Liu teaches that 50-200 mM arginine may be used in antibody formulations for the same purpose; thus encompassing a formulation of 100 mM arginine. It is obvious for one of skill in the art to perform routine optimization of buffers with overlapping ranges to find the most beneficial formulations for their purpose; see MPEP section 2144.05. Thus, the invention of claims 29-30 were prima facie obvious to one of skill in the art over the combination of Liang, Blake-Haskins and Liu et al.
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 1-9, 11, 13, 15, 17, 21-23, 25-26, 28-30, 38, 40 and 58-60 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,152,084; issued 11/26/2024 in view of Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020).
Patent ‘084 claims a method of treatment for cancer in a patient comprising administering the triple combination comprising an anti-TIGIT antibody, an anti-PVRIG antibody and an anti-PD-1 antibody wherein the anti-TIGIT antibody is CPA.9.083.H4(S241P) or CPA.9.086.H4(S241P) (claims 1-3); wherein the anti-PVRIG antibody is CHA.7.518.1.H4(S241P) (claim 4); wherein the anti-PD-1 antibody is one of pembrolizumab, cemiplimab or nivolumab (claim 5); whereby the antibodies are administered simultaneously (claim 6) or separately (claim 7), or sequentially (claim 8); whereby the antibodies are administered sequentially over a period of hours or days (claim 9); whereby the cancer is ovarian cancer (claims 10-11). Patent a'084 also claims wherein the antibodies are provided in a kit with dosage units of each antibody either packaged separately in individual dosage units, or together, as a mixture of antibodies as a single dosage unit (claim 12).
As described above, Liang et al teaches a triple combination therapy for cancer treatment comprising an anti-TIGIT antibody, an anti-PVRIG antibody and an anti-PD-1 antibody. Liang teaches the anti-TIGIT antibody may be CPA.9.083.H4(S241P), among others, (see Liang pg. 70, claims 63-64), including 22G2, which is BMS-986207, as described above; (see Liang pg. 24, para. 0254 for teaching antibody 22G2). Liang teaches the anti-PVRIG antibody may be CHA.7.518.1.H4(S241P), among others, (see Liang pg. 70, claims 63-64). Liang teaches the anti-PD-1 antibody may be pembrolizumab, cemiplimab or nivolumab (see Liang pg. 70, claim 62). Thus, as Liang teaches a triple combination method for treating cancer, whereby different species of each of the anti-TIGIT, anti-PVRIG and anti-PD-1 antibodies are suitable, it is obvious to substitute the different species in the triple combination method of Liang to arrive at the anti-TIGIT antibody of BMS-986207, the anti-PVRIG antibody of CHA.7.518.1.H4(S241P) and the anti-PD-1 antibody of nivolumab, of instant claim 1.
Blake-Haskins teaches formulations for antibodies in high concentration, as described above. Blake-Haskins teaches adding histidine, NaCl, L-Arginine and polysorbate 80, with a pH of 6.0±0.5. Further, Blake-Haskins teaches increasing the amount of arginine to improve stability over time, specifically designating arginine as the formulation “stabilizer”; such that it would have been obvious to the skilled artisan to increase the amount of arginine to 100 mM under routine optimization of formulations taught in the art, with motivation to increase stability, as taught by Blake-Haskins, and as described above. Thus, Blake-Haskins makes obvious the formulation of the triple combination antibody therapy of Liang, of instant claim 1, and instant claims 29-30.
Specifically, the triple combination method of patent ‘084 claims 1-5, over Liang and Blake-Haskins, makes obvious the method of instant claims 1 and 3-4, comprising the structures of claims 5-8, 25-26 and 28, comprising the formulation and inherent properties of claims 9, 11, 13, 15, 17, 21-23 and 29-30; comprising the methods for measuring and properties of treatment efficacy of claims 38, 40 and 58-59. Patent ‘084, claims 6-9, over Liang and Blake-Haskins, makes obvious instant claim 2. Patent ‘084, claims 10-11, over Liang and Blake-Haskins, makes obvious wherein the cancer is ovarian cancer of instant claim 60.
Claims 1-9, 11, 13, 15, 17, 20-26, 28-38, 40 and 58-60 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,152,084 in view of Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020) and Maurer et al., (from IDS, Cite No. A123; WO 2016106302; published 6/30/2016).
The reasons why claims 1-9, 11, 13, 15, 17, 21-23, 25-26, 28-30, 38, 40 and 58-60 are made obvious over the combination of patent ‘084, Liang and Blake-Haskins is described above. However, the combination of ‘084, Liang and Blake-Haskins does not teach the formulation concentration of antibodies, the dosing concentration of antibodies nor the administration regime of the instant claims (i.e., re. claims 20, 24 and 31-37).
Maurer teaches art-recognized standards for antibody formulation concentrations, dosing concentrations and administration regimes for methods of treating cancer. The specific limitations, and citations within Maurer are provided above.
The combination of patent ‘084, Liang, Blake-Haskins and Maurer make obvious instant claims 20, 24 and 31-37.
As described above, Liang teaches triple combination therapies for treating cancer comprising an anti-TIGIT antibody, an anti-PVRIG antibody and an anti-PD-1 antibody, whereby various alternative species for each antibody are listed and are substitutable. Specifically, Liang teaches the anti-TIGIT antibody may be any one of 22G2, CPA.9.083.H4(S241P), CPA.9.086.H4(S241P), CPA.9.547.7.H4(S241P) or CPA.9.547.13.H4(S241P); the anti-PVRIG antibody may be any one of CHA.7.518.1.H4(S241P) or CHA.7.538.1.2.H4(S241P); and the anti-PD-1 antibody may be any one of pembrolizumab, cemiplimab, and nivolumab.
Blake-Haskins teaches the formulations comprising histidine, NaCl, arginine, polysorbate at a pH of 6.0±0.5; and Maurer teaches standard, art recognized antibody concentrations as well as dosing and administration regimes for administering antibody therapy for treatment of cancer. The combination of Liang, Blake-Haskins and Maurer make obvious each of the instant claims as described in the prior art 103 rejections above.
Therefore, any co-pending application or issued patent that claims the anti-TIGIT antibodies or the anti-PVRIG antibodies makes obvious the instant claims in view of the triple combination method of treating cancer of Liang, over Blake-Haskins and Maurer.
Claims 1-9, 11, 13, 15, 17, 20-26, 28-38, 40 and 58-60 are rejected (in the case of issued patents), or provisionally rejected (in the case of pending applications) over the listed claims of the following U.S. Patents and pending applications, in view of Liang et al., (US 2019/0010246; published 1/10/2019 and Blake-Haskins et al., (US Patent 10,556,009; issued 2/11/2020) and Maurer et al., (from IDS, Cite No. A123; WO 2016106302; published 6/30/2016).
Below is a Table listing patents and/or co-pending applications, which name a common inventor, and which claim an anti-TIGIT antibody or an anti-PVRIG antibody (or both; with or without a PD-1 antibody), whereby the claims would make obvious, over Liang, Blake-Haskins and Maurer, instant claim 1, and all dependent claims, for the same reasons why Liang, Blake-Haskins and Maurer make obvious the instant claims as described above.
U.S. Patent or co-pending U.S. application
Claims
Comment
10751415
1-9
TIGIT ab composition with PD-1 or PVRIG
10124061
1-9
Method of activating T cells with TIGIT ab + PD-1 or PVRIG
10213505
1-2
PVRIG ab composition
11225523
71-72, 74-82
Liang et al. triple combination method
11701424
1-4, 9-12, 17-30
Method of activating T cells with PVRIG ab + PD-1
12152084
60-71
Liang et al. triple combination method
18/322545
31, 34-37, 40-43, 47
TIGIT ab nucleic acids composition
18/452985
82-101
TIGIT ab composition
18/774872
59-65, 67-73
Liang et al. triple combination method
17/782635
1-45
Method of activating NK cells with PVRIG and TIGIT abs.
18/185632
1, 7, 12, 16, 23, 47-48, 63, 65, 71, 73, 75-79, 194-196
PVRIG ab for treating cancer, claim 1(c)
18/263171
1, 36, 68-71, 88-89, 101-102
PVRIG ab formulation, treatment of cancer
18/263172
1, 36-39,56-57, 69-70
PVRIG ab formulation, treatment of cancer
18/572125
1-5, 8, 24, 29-30, 35, 37, 43, 76, 78, 123, 133, 150
Method for treating cancer with PVRIG and TIGIT abs.
18/700194
1-2, 4-5, 7-9, 11-16, 19-22, 24, 26, 28, 30, 33-43, 45-49, 51, 53, 55, 74-75
Method for treating cancer with PVRIG, TIGIT and PD-1 abs.
19/099045
1-120
Method of treating cancer with PVRIG and PD-1 abs.
19/159457
1-62; from PRO 63/487230
PVRIG, TIGIT abs + Pembrolizumab
19/205900
1-2, 4-6, 8-9, 15, 17, 19, 21, 23, 26-27, 38, 40, 43, 58-59, 159
Method of maintenance treatment for cancer with PVRIG, TIGIT abs and pembrolizumab.
18/868661
1-2, 4-13, 16-23, 25-26
TIGIT ab formulation, method for treating cancer.
10227408
33-52
PVRIG ab composition
9714289
22-41
Method of activating T cells with PVRIG ab composition
11220542
23-64
Method of activating T cells with PVRIG ab composition
10351625
21-59
Method of activating T cells with PVRIG ab + PD-1 ab composition
11623955
1-33
Method of activating NK cells with PVRIG ab
11795220
1-24
Method of activating T cells with PVRIG ab + PD-L1 ab composition
12312404
38-53
PVRIG ab composition
19/190452
38-61
PVRIG ab composition
16/428856
4-11, 16, 87, 90-91
Anti-PVRIG/anti-TIGIT bispecific ab
17/631847
1-23, 25-30
PVRIG ab formulation
17/773791
1-5, 7, 9, 11, 13-23, 25-32
Method of treating cancer with PVRIG ab + PD-L1 ab composition
18/249957
1-2, 4, 8, 10, 103, 112, 116,
PVRIG ab for treating cancer, claim 1(c)
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normal