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 .
Application Status
Claims 23-43 are pending.
Claim 32 is withdrawn.
Claims 23-31 and 33-43 are examined on the merits herein.
Grounds of Rejection Withdrawn
The objection to the specification has been withdrawn in view of amendments to the specification.
Previous rejection of claim 29 under U.S.C. 102 is withdrawn in view of claim amendments.
Previous rejection of claims 30 and 31 under U.S.C. 103 is withdrawn in view of claim amendments.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See page 84, lines 9 and 10.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms BiTE® and DVD™, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 38 and 41 are objected to because of the following informalities:
Claims 38 and 41 contains the terms BiTE® and DVD™ without the appropriate registered trademark symbol.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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.
Claims 23-26, 29, 33-37, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (US 2016/0177276 A1; cited in last office action) and Lin (WO 2018/176132 A1; IDS entered June 17, 2021).
Regarding claim 23, Lo teaches an immunoglobulin fusion protein comprising a SIRPα moiety that binds to CD47 and an antigen binding site for a tumor cell antigen (abstract). As seen in Figure 1 Lo teaches a fusion molecule with SIRPa at the C or N terminus of the immunoglobin. Lo further teaches the immunoglobulin fusion proteins of the invention can be specific for any tumor antigen. Exemplary tumor cell antigens include but are not limited to: …PD-1…(paragraph 0157). Lo further teaches in some embodiments the antigen binding domain is an antigen-binding fragment (para 0036).
Regarding claim 24, Lo teaches in yet other embodiments, an antibody includes an intact antibody or antigen-binding fragment of an antibody (e.g., a phage display antibody including a fully human antibody,..)(paragraph 0142).
Regarding claim 25-26, Lo teaches a SIRPα immunoglobulin fusion protein comprising: an IgV extracellular domain of SIRPα or a SIRPα variant comprising an amino acid sequence at least 80% identical to residues 3-115 of SEQ ID NO:6 (claim 1), with 100% sequence identity to the instant claimed SEQ ID NO: 51.
Regarding claim 29, Lo teaches in some embodiments, antibodies may be IgG1, IgG2, IgG3, IgG4, IgM, IgE, IgD, or IgA (paragraph 0142).
Regarding claim 33, Lo teaches a nucleic acid or nucleic acids encoding the immunoglobulin fusion protein of any one of claim 1 (claim 66).
Regarding claim 34, Lo teaches although exemplary methods of fusion protein expression and production are described in, for example, Examples 2 and 4 below, a wide variety of suitable vectors, cell lines and protein production methods have been used to produce biopharmaceuticals and could be used in the synthesis of the fusion proteins of the invention. Such methods are within the knowledge of the skilled artisan (paragraph 0177).
Regarding claim 35, Lo teaches a cell comprising the nucleic acid or nucleic acids of claim 66 (claim 67).
Regarding claim 36, Lo teaches a method of producing an immunoglobulin fusion protein by maintaining the cell of claim 67 under conditions that permit expression of the nucleic acid or nucleic acids (claim 68).
Regarding claim 37, Lo teaches a pharmaceutical composition comprising a pharmaceutically effective amount of the immunoglobulin fusion protein of claim 1 and a pharmaceutically acceptable carrier (claim 69).
Regarding claim 39, Lo teaches a method of treating cancer in a mammal comprising administering an effective amount the immunoglobulin fusion protein of claim 1 to a mammal in need thereof (claim 70).
Regarding claim 40, Lo teaches in yet a further aspect, the invention is directed to methods of treating cancer by administering an effective amount of an immunoglobulin fusion protein described herein. The cancers that can be treated include breast, colorectal, lung, pancreatic, endometrial, ovarian, gastric, prostate, renal, cervical, myeloma, lymphoma, leukemia, thyroid, uterine, bladder, neuroendocrine, head and neck, liver, nasopharyngeal, testicular, small cell lung cancer, non-small cell lung cancer, melanoma, basal cell skin cancer, squamous cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, glioblastoma, glioma, sarcoma, mesothelioma, or myelodysplastic syndromes (paragraph 0061).
Lo does not teach the specific PD-1 antibody.
Lin teaches a combination treatment for cancer comprising an anti-PD-1 antibody, specifically nivolumab, and a soluble SIRP alpha-Fc fusion molecule (claims 1-4, 10-13 and 20).
Lin further teaches Nivolumab is an approved human IgG4 antibody that binds
human PD-1 for use as first line treatment for inoperable or metastatic melanoma (para 0052). Lin further teaches it is now found that the anti-cancer effect of a SIRPa-based CD47 blockade drug is improved when combined with an agent that inhibits a T cell checkpoint, such as agents that inhibit the programmed death-1 (PD-1) (para 0007); wherein the T cell checkpoint inhibitor and the CD47 blockade drug are present or used in synergistically effective amounts (claim 33; Figure 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply substitute nivolumab as taught by Lin into the bifunctional PD-1 antibody fragment – SIRP alpha Fc fusion molecule taught by Lo. The ordinary artisan would have been motivated to do so because as Lin teaches that nivolumab is an approved treatment for metastatic melanoma and that combination treatment with nivolumab and an anti SIRP alpha Fc fusion act synergistically for cancer. This is a simple substitution of a known approved antibody into the fusion molecule as taught Lo that has already demonstrated synergistic benefits in combination therapy and therefore the ordinary artisan has a reasonable expectation of success.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Lo (US 2016/0177276 A1; cited in last office action) and Lin (WO 2018/176132 A1; IDS entered June 17, 2021) as applied to claims 23-26, 29, 33-37, and 39-40 above, and further in view of Hinton (J Immunol, 2006, 176(1): 346-56; cited in last office action).
The teachings of Lo and Lin are detailed above.
Lo and Lin do not teach the bifunctional molecule wherein the antibody or antigen- binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P33IS; E333A; S239D/A330L/I332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and K444A.
Hinton teaches that T250Q/ M428L mutations in IgG1 improves FcRn binding (Table II) that improves antibody serum half-life (discussion). Hinton further teaches that Ag binding was unaffected by the Fc mutations, while several effector functions appeared to be minimally altered (abstract). Hinton further teaches that these properties suggest that engineered Abs with longer serum half-lives may prove to be effective therapeutics in humans (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the IgG mutations as taught by Hinton to the bifunctional nivolumab – SIRP alpha Fc fusion molecules as taught by Lo and Lin. The ordinary artisan would have been motivated to do so because as Hinton teaches that the T250Q/ M428L mutations in IgG1 improves FcRn binding and that improves antibody serum half-life which may prove to be effective therapeutics in humans.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Lo (US 2016/0177276 A1; cited in last office action) and Lin (WO 2018/176132 A1; IDS entered June 17, 2021) as applied to claims 23-26, 29, 33-37, and 39-40 above, and further in view of Newman (Clin Immunol. 2001 Feb;98(2):164-74; cited in last office action).
The teachings of Lo and Lin are detailed above.
Lo and Lin do not teach wherein the antibody or antigen- binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P; L234A/L235A, S228P + M252Y/S254T/T256E and K444A.
Newman teaches that modification of IgG4 to contain proline and glutamic acid substitutions at residues 228 and 235, respectively, resulted in an IgG4 that was not only devoid of Fcγ receptor binding activity, but was stable in vitro and in vivo and showed CD4 receptor modulation but did not result in depletion of CD4+ T cells, giving the desired profile for clinical study (discussion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the IgG mutations as taught by Newman to the bifunctional nivolumab and SIRP alpha Fc fusion molecule as taught by Lo and Lin. The ordinary artisan would have been motivated to do so because as Newman teaches that modification of IgG4 to contain proline and glutamic acid substitutions at residues 228 and 235, respectively, resulted in an IgG4 that was not only devoid of Fcγ receptor binding activity, but was stable in vitro and in vivo and showed CD4 receptor modulation but did not result in depletion of CD4+ T cells, giving the desired profile for clinical study.
Double Patenting
Rejection Maintained
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 23-31, 33-37 and 39-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,352,430 B2 in view of Lo (US 2016/0177276 A1; cited in last office action) and Kauder (PLOS One, 2018, 13(8): e0201832; cited in last office action).
Regarding claims 23-24 and 27-28 the patented claims teach a humanized monoclonal anti-human-PD-1 antibody or an antigen-binding fragment thereof comprising: (a) a VH comprising or consisting of an amino acid sequence of SEQ ID NO: 21; and (b) a VL comprising or consisting of an amino acid sequence of SEQ ID NO: 24, wherein the antibody or antigen binding fragment thereof is an antagonist of the binding of human PD-L1 and/or PD-L2 to human PD-1 (claim 1). The claimed SEQ ID NO: 21 has 100% sequence identity to the instant claimed SEQ ID NO: 24, which contains CDRs comprising SEQ ID NOs: 1, 2, and 10. The claimed SEQ ID NO: 24 has 100% sequence identity to the instant claimed SEQ ID NO: 28 which contains CDRs comprising SEQ ID NOs: 14-16.
Regarding claim 29, the patented claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 3).
Regarding claim 30, the patented claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/I332E; P257I/Q311; K326W/E333S; S239D/I332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A and K444A, preferably selected from the group consisting of N297A optionally in combination with M252Y/S254T/T256E, and L234A/L235A (claim 4).
Regarding claim 31, the patented claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P; L234A/L235A, S228P+M252Y/S254T/T256E and K444A (claim 5).
Regarding claim 33, the patented claims teach an isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding the antibody or antigen-binding fragment of claim 1 (claim 7).
Regarding claim 34, the patented claims teach a vector comprising the isolated nucleic acid molecule or the group of isolated nucleic acid molecules of claim 7 (claim 8).
Regarding claim 35, the patented claims teach a host cell comprising the isolated nucleic acid molecule and/or the group of isolated nucleic acid molecules of claim 7 and/or the vector comprising said nucleic acid molecule or group of nucleic acid molecules (claim 9).
Regarding claim 36, the patented claims teach a method for producing antibody or antigen-binding fragment thereof comprising a step of culturing a host cell according to claim 9 and optionally a step of isolating the antibody or antigen-binding fragment (claim 10).
Regarding claim 37, the patented claims teach a pharmaceutical composition comprising an antibody or an antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier (claim 11).
Regarding claims 39-40, the patented claims teach a method of treating cancer in a subject comprising administering an antibody or antigen binding fragment of claim 1, or a composition comprising said antibody or antigen binding fragment and a pharmaceutically acceptable excipient, to a subject having cancer, said cancer being selected from the group consisting of malignant mesothelioma, colorectal cancer and hepatocellular carcinoma (claim 12).
Regarding claim 41, the patented claims teach wherein said antibody, antigen binding fragment or composition is administered in combination with radiotherapy or an additional therapeutic (claim 14).
The patented claims do not teach a bifunctional molecule comprising the anti-human PD-1 antibody and a SIRPa protein or the sequence thereof.
Regarding claim 23, Lo teaches an immunoglobulin fusion protein comprising a SIRPα moiety that binds to CD47 and an antigen binding site for a tumor cell antigen (abstract). As seen in Figure 1 Lo teaches a fusion molecule with SIRPa at the C or N terminus of the immunoglobin. Lo further teaches the immunoglobulin fusion proteins of the invention can be specific for any tumor antigen. Exemplary tumor cell antigens include but are not limited to: …PD-1…(paragraph 0157).
Regarding claim 25-26, Lo teaches a SIRPα immunoglobulin fusion protein comprising: an IgV extracellular domain of SIRPα or a SIRPα variant comprising an amino acid sequence at least 80% identical to residues 3-115 of SEQ ID NO:6 (claim 1).
Kauder teaches that in a colon carcinoma model combination treatment with ALX148 (a SIRPaD1-Fc fusion protein) and an anti-PD-1 antibody resulted in enhanced antitumor efficacy, extended survival, and persistence of antitumor immune responses (page 17, paragraph 1 and page 27, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the treatment of cancer with the anti-PD-1 antibody as taught by the patented claims with the SIRPa protein into a bifunctional molecule as taught by Lo and Kauder. The ordinary artisan would have been motivated to do so because as Kauder teaches that combination of a SIRPa protein with an anti-PD-1 antibody enhanced antitumor efficacy, extended survival, and persistence of antitumor immune responses and Lo teaches a fusion protein comprising a SIRPa moiety that binds to CD47 fused to an immunoglobulin that can be PD-1. It would be a simple substitution to use the sequence of the anti PD-1 antibody of the patented claims into the fusion molecule of Lo to generate a bifunctional molecule with a reasonable expectation of enhanced antitumor efficacy and extended survival versus the either of the single elements.
Claim 38 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,352,430 B2 in view of Lo (US 2016/0177276 A1; cited in previous office action) and Kauder (PLOS One, 2018, 13(8): e0201832; cited in previous office action) as applied to claims 23-31, 33-37 and 39-41 above, and further in view of Liu (Nat Med 21, 1209–1215 (2015); cited in previous office action).
The teachings of the patented claims, Lo and Kauder are detailed above.
The patented claims, Lo, and Kauder do not teach wherein the pharmaceutical composition further comprises an additional therapeutic or administration of the pharmaceutical composition in combination therapy.
Regarding claim 38, Liu teaches combined anti-CD47 treatment with clinically equivalent doses of cyclophosphamide (CTX) or paclitaxel (PTX) and found that a single treatment of chemotherapy before anti-CD47 not only synergized with anti-CD47 for tumor control but also preserved the host memory response against relapsing tumors generated by anti-CD47 (page 1214, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add platinum based chemotherapy as taught by Liu to the treatment of cancer with a bifunctional molecule as taught by Lo. The ordinary artisan would have been motivated to do so because Liu teaches that administration of paclitaxel synergized with anti-CD47 treatment resulting in tumor control and host memory preservation. Therefore addition of paclitaxel to the anti-PD-1 and SIRPa bifunctional molecule composition and treatment would be reasonably expected to result in a therapeutic benefit to cancer patients.
Claims 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,352,430 B2 in view of Lo (US 2016/0177276 A1; cited in previous office action) and Kauder (PLOS One, 2018, 13(8): e0201832; cited in previous office action) as applied to claims 23-31, 33-37 and 39-41 above, and further in view of Rao (Int J Infect Dis. 2017 Mar;56:221-228; cited in previous office action).
The teachings of the patented claims, Lo, and Kauder are detailed above.
Lo further teaches that macrophages are the principal phagocytes that clear diseased cells and that there is a need for therapies that interfere with tumor cells' ability to avoid phagocytosis through expression of CD47 as cancer cells adapt to enhance their survival, they subvert normal immune control mechanisms to escape immune surveillance by over-expressing CD47, rendering them resistant to macrophages (Background).
The patented claims and Lo do not teach a method of treating an infectious disease, a chronic infectious disease, or chronic viral infections comprising the administration of a composition or wherein the infectious disease is caused by a virus selected from the group consisting of HIV, hepatitis virus, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
Rao teaches that the phenomenon of T-cell exhaustion in chronic infections is similar to cancer and therefore anti-PD-1 antibodies should be trialed in the treatment of severe chronic infectious disease given their success in cancer treatment (page 225, column 1, paragraph 2). Rao further teaches that PD-1 blockade reversed T-cell exhaustion while reducing viral load as well as various opportunistic infections in a non-human primate model of simian immunodeficiency virus infection for HIV infection (page 225, column 1, paragraph 4). Rao further teaches PD-1 blockade appears to augment reduced hyper-activation of type 1 IFN responses, which in part translates to a lower incidence of systemic cytokine storms and immune dysregulation in HIV infection,61 which can reduce tissue pathology in patients (page 225, column 1, paragraph 4). Rao further teaches that patients with chronic HCV infection treated with nivolumab were reported to respond well, some achieving more than a 4-log reduction in viral load after treatment (page225, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat chronic infectious disease as taught by Rao with the bifunctional molecules as taught by the patented claims, Lo and Kauder. The ordinary artisan would have been motivated to do so because as Rao teaches that patients with chronic HCV infection treated with nivolumab were reported to respond well, some achieving more than a 4-log reduction in viral load after treatment. Lo teaches that SIRPa fusion protein would activate phagocytosis by macrophages to clear diseased cells. Therefore treatment with the bifunctional molecule would provide a therapeutic benefit to patients suffering from chronic infections.
Claims 23-24, 27-31, and 33-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-47 of copending Application No. 17/414,968 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 23-24, and 27, the copending claims teach a bifunctional molecule consisting of: (a) a humanized anti-human PD-1 antibody or antigen-binding fragment thereof, which comprises: (i) a heavy chain variable domain (VH) comprising HCDR1, HCDR2 and HCDR3, and (ii) a light chain variable domain (VL) comprising LCDR1, LCDR2 and LCDR3, wherein: - the heavy chain CDR1 (HCDR1) comprises or consists of an amino acid sequence of SEQ ID NO: 1; - the heavy chain CDR2 (HCDR2) comprises or consists of an amino acid sequence of SEQ ID NO: 2; - the heavy chain CDR3 (HCDR3) comprises or consists of an amino acid sequence of SEQ ID NO: 3 wherein X1 is D or E and X2 is selected from the group consisting of T, H, A, Y, N, E and S, preferably in the group consisting of H, A, Y, N, and E;- the light chain CDR1 (LCDR1) comprises or consists of an amino acid sequence of SEQ ID NO: 12 wherein X is G or T; - the light chain CDR2 (LCDR2) comprises or consists of an amino acid sequence of SEQ ID NO: 15, - the light chain CDR3 (LCDR3) comprises or consists of an amino acid sequence of SEQ ID NO:16, and (b) an immunotherapeutic agent or a fragment thereof, wherein the C-terminal end of the heavy and/or light chain(s) of the antibody or antigen-binding fragment thereof is covalently linked to the N-terminal end of the immunotherapeutic agent as a fusion protein, preferably by a peptide linker (claim 25), wherein the immunotherapeutic agent is a human transmembrane immune protein of type I or a fragment thereof, preferably selected from the group consisting of …, SIRPalpha, … (claim 30). The claimed SEQ ID NO: 1, 2, 3, 12, 15, 16 are identical to the instant claimed SEQ ID NOs. The elected species in the instant application SEQ ID NO: 10 is one of the options of wildcards for SEQ ID NO: 3. The elected species in the instant application SEQ ID NO: 14 is one of the options for the wildcard in SEQ ID NO: 12.
Regarding claim 28, the copending claims teach wherein the humanized anti-human PD-1 antibody or antigen- binding fragment thereof, comprises (a) a VH comprising or consisting of an amino acid sequence of SEQ ID NO: 17, wherein X1 is D or E and X2 is selected from the group consisting of T, H, A, Y, N, E and S preferably in the group consisting of H, A, Y, N and E; and (b) a VL comprising or consisting of an amino acid sequence of SEQ ID NO: 26, wherein X is G or T (claim 26). The elected species in the instant application SEQ ID NO: 24 is one of the options of wildcards for SEQ ID NO: 17. The elected species in the instant application SEQ ID NO: 28 is one of the options for the wildcard in SEQ ID NO: 26.
Regarding claim 29, the copending claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1,IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34).
Regarding claim 30, the copending claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A and K444A, preferably selected from the group consisting of N297A optionally in combination with M252Y/S254T/T256E, L234A/L235A (claim 35).
Regarding claim 31, the copending claims teach wherein the antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P; L234A/L235A, S228P + M252Y/S254T/T256E and K444A (claim 36).
Regarding claim 33, the copending claims teach an isolated nucleic acid sequence or a group of isolated nucleic acid molecules encoding the bifunctional molecule of claim 25 (claim 37).
Regarding claim 34, the copending claims teach a vector comprising the nucleic acid or group of nucleic acid molecules of claim 37 (claim 38).
Regarding claim 35, the copending claims teach a host cell comprising the nucleic acid or group of nucleic acid molecules of claim 37 or a vector comprising said nucleic acid or group of nucleic acids (claim 39).
Regarding claim 36, the copending claims teach a method for producing the bifunctional molecule comprising a step of culturing a host cell of claim 39 and optionally a step of isolating the bifunctional molecule (claim 40).
Regarding claim 37, the copending claims teach a pharmaceutical composition comprising the bifunctional molecule of claim 25 and a pharmaceutically acceptable carrier (claim 41).
Regarding claim 38, the copending claims teach the pharmaceutical composition of claim 41, wherein the pharmaceutical composition further comprises an additional therapeutic agent selected from the group consisting of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, Bruton's tyrosine kinase (BTK) inhibitors, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, hypomethylating agents, checkpoints inhibitors, peptide vaccine, epitopes or neoepitopes from tumor antigens, and combinations of one or more of these agents (claim 42).
Regarding claim 39, the copending claims teach a method of treating cancer comprising the administration of a pharmaceutical composition of claim 41 to a subject in need of treatment (claim 43).
Regarding claim 40, the copending claims teach the method of claim 43, wherein the cancer is selected from the group consisting of a hematologic malignancy or a solid tumor with expression of PD-1 and/or PD-L1, hematolymphoid neoplasms, angioimmunoblastic T cell lymphoma, myelodysplastic syndrome, and acute myeloid leukemia, a cancer induced by virus or associated with immunodeficiency, Kaposi sarcoma, cervical, anal, penile and vulvar squamous cell cancer and oropharyngeal cancers. B cell non-Hodgkin lymphomas (NHL), diffuse large B-cell lymphoma, Burkitt lymphoma, plasmablastic lymphoma, primary central nervous system lymphoma, HHV-8 primary effusion lymphoma, classic Hodgkin lymphoma, and lymphoproliferative disorders, hepatocellular carcinoma, Merkel cell carcinoma, cancer associated with human immunodeficiency virus infection (HIV) infection, a metastatic or nonmetastatic cancer, Melanoma, malignant mesothelioma, Non-Small Cell Lung Cancer, Renal Cell Carcinoma, Hodgkin's Lymphoma, Head and Neck Cancer, Urothelial Carcinoma, Colorectal Cancer, Hepatocellular Carcinoma, Small Cell Lung Cancer, Metastatic Merkel Cell Carcinoma, Gastric or Gastroesophageal cancers and Cervical Cancer (claim 44).
Regarding claim 41, the copending claims teach the method of claim 43, said method comprising the administration of said composition in combination with radiotherapy or an additional therapeutic agent selected from the group consisting of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, Bruton's tyrosine kinase (BTK) inhibitors, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, hypomethylating agents, checkpoints inhibitors, peptide vaccine, epitopes or neoepitopes from tumor antigens, and combinations of one or more of these agents (claim 45).
Regarding claim 42, the copending claims teach a method of treating infectious disease, chronic infectious disease, or chronic viral infections comprising the administration of a composition of claim 41 to a subject in need of treatment (claim 46).
Regarding claim 43, the copending claims teach the method of claim 46, wherein the infectious disease is caused by a virus selected from the group consisting of HIV, hepatitis virus, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus (claim 47).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-47 of copending Application No. 17/414,968 (reference application) as applied to claims 23-24, 27-31, and 33-43 above, and further in view of Lo (US 2016/0177276 A1; cited in previous office action).
The teachings of the copending claims are detailed above.
The copending claims do not teach that the SIRPa is the extracellular domain or the sequence thereof.
Regarding claim 23, Lo teaches an immunoglobulin fusion protein comprising a SIRPα moiety that binds to CD47 and an antigen binding site for a tumor cell antigen (abstract). As seen in Figure 1 Lo teaches a fusion molecule with SIRPa at the C or N terminus of the immunoglobin. Lo further teaches the immunoglobulin fusion proteins of the invention can be specific for any tumor antigen. Exemplary tumor cell antigens include but are not limited to: …PD-1…(paragraph 0157).
Regarding claims 25-26, Lo teaches a SIRPα immunoglobulin fusion protein comprising: an IgV extracellular domain of SIRPα or a SIRPα variant comprising an amino acid sequence at least 80% identical to residues 3-115 of SEQ ID NO:6 (claim 1), with 100% sequence identity to the instant claimed SEQ ID NO: 51.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the sequence of SIRPa as taught by Lo into the bifunctional molecule as taught by the copending claims. The ordinary artisan would have been motivated to do so because as it would be a simple substitution to use the sequence of the SIRPa protein of Lo into the bifunctional molecule of the copending claims to generate a bifunctional molecule with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 23, 25, 27, 33, 35, 37, and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of copending Application No. 18/285,664 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 23 and 25, the copending claims teach a bifunctional molecule comprising a single antigen binding domain that binds to a target specifically expressed on immune cells surface and a single immune-stimulating moiety, wherein the molecule comprises a first monomer comprising an antigen-binding domain covalently linked via C-terminal end to N-terminal end of a first Fc chain, optionally via a peptide linker, and a second monomer comprising a complementary second Fc chain devoid of antigen-binding domain and of the immune-stimulating moiety; wherein either i) the immune-stimulating moiety is covalently linked to the C-terminal end of said first Fc chain, optionally via a peptide linker; or ii) the single antigen binding domain comprises a heavy variable chain and a light variable chain and the immune-stimulating moiety is covalently linked to the C-terminal end of the light chain; wherein the target specifically expressed on immune cells surface is selected from the group consisting of PD-1, …; and wherein the immune-stimulating moiety is selected from the group consisting of … SIRPa, … or a fragment thereof comprising the extracellular part thereof or a variant thereof having at least 80% of identity with the wildtype protein or the extracellular part thereof (claim 17), wherein the immune-stimulating moiety is SIRPa, or a fragment thereof comprising the extracellular part thereof or a variant thereof having at least 80% of identity with the wildtype protein or the extracellular fragment thereof (claim 18), wherein the immune-stimulating moiety is linked at the C-terminal end of first Fc chain (claim 20), wherein the immune-stimulating moiety is linked at the C-terminal end of the light chain (claim 21), wherein the antigen binding domain binds to PD-1 (claim 25) and wherein the antigen binding domain comprises: (i) a heavy chain comprising a CDR1 of SEQ ID NO: 51, a CDR2 of SEQ ID NO: 53 and a CDR3 of SEQ ID NO: 55, 56, 57, 58, 59, 60, 61 or 62; and (ii) a light chain co