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 .
Applicant’s amendment filed on 3/23/2026 is acknowledged.
Claims 31-53 are pending. Claims 1-30 are cancelled.
Information Disclosure Statement
The references in the information disclosure statements (IDS) filed on 8/30/2023 and 3/23/2026 have been considered.
Election/Restrictions
Applicant’s election without traverse of the species of the method of treating an ovarian cancer and a clear cell carcinoma comprising administering a PD-1 x CTLA-4 bispecific antibody with an Fc IgG4 isotype with amino acid substitutions (a) reducing the affinity of variant Fc region to an FcyR and (b) M252Y, S254T, and T256E and one chemotherapeutic agent in the reply filed on 3/23/2026 is acknowledged.
Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/23/2026.
Claims 31-47 and 49-53 are currently under consideration as they read on a method of treating ovarian cancer and clear cell carcinoma comprising administering a PD-1 x CTLA-4 bispecific molecule with an Fc IgG4 isotype with amino acid substitutions (a) reducing the affinity of variant Fc region to an FcyR and (b) M252Y, S254T, and T256E and one chemotherapeutic agent.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 31, 39-46, and 51 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 31, 39-46, and 51 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. The specific dosing regimen including specific dosage(s) and specific length of timing of administration (induction and maintenance periods) of the PD-1 x CTLA-4 bispecific antibody remains unclear.
Appropriate correction is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 31-47 and 49-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: a method of treating ovarian cancer and clear cell carcinoma comprising administering a PD-1 x CTLA-4 bispecific molecule with a VHPD-1 of SEQ ID NO:5 comprising CDRH1, 2, and 3 with SEQ ID NOs:6, 7, and 8, respectively, and a VLPD-1 of SEQ ID NO:1 comprising CDRL1, 2, and 3 with SEQ ID NOs:2, 3, and 4, respectively; and a VHCTLA-4 of SEQ ID NO:13 comprising CDRH1, 2, and 3 with SEQ ID NOs:14, 15, and 16, respectively, and a VLCTLA-4 of SEQ ID NO:9 comprising CDRL1, 2, and 3 with SEQ ID NOs:10, 11, and 12, respectively; wherein, the bispecific molecule contains two polypeptide chains of SEQ ID NO:40 and two polypeptide chains of SEQ ID NO:41; a method of stimulating T cells comprising a PD-1 x CTLA-4 bispecific molecule with a VHPD-1 of SEQ ID NO:5 comprising CDRH1, 2, and 3 with SEQ ID NOs:6, 7, and 8, respectively, and a VLPD-1 of SEQ ID NO:1 comprising CDRL1, 2, and 3 with SEQ ID NOs:2, 3, and 4, respectively; and a VHCTLA-4 of SEQ ID NO:13 comprising CDRH1, 2, and 3 with SEQ ID NOs:14, 15, and 16, respectively, and a VLCTLA-4 of SEQ ID NO:9 comprising CDRL1, 2, and 3 with SEQ ID NOs:10, 11, and 12, respectively; wherein, the bispecific molecule contains two polypeptide chains of SEQ ID NO:40 and two polypeptide chains of SEQ ID NO:41; and a pharmaceutical kit comprising a container comprising a PD-1 x CTLA-4 bispecific molecule with a VHPD-1 of SEQ ID NO:5 comprising CDRH1, 2, and 3 with SEQ ID NOs:6, 7, and 8, respectively, and a VLPD-1 of SEQ ID NO:1 comprising CDRL1, 2, and 3 with SEQ ID NOs:2, 3, and 4, respectively; and a VHCTLA-4 of SEQ ID NO:13 comprising CDRH1, 2, and 3 with SEQ ID NOs:14, 15, and 16, respectively, and a VLCTLA-4 of SEQ ID NO:9 comprising CDRL1, 2, and 3 with SEQ ID NOs:10, 11, and 12, respectively; wherein, the bispecific molecule contains two polypeptide chains of SEQ ID NO:40 and two polypeptide chains of SEQ ID NO:41; a method of stimulating T cells comprising.
Applicant is not in possession of: a method of treating cancer comprising administering a PD-1 x CTLA-4 bispecific molecule wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 binding domain and a CTLA-4 binding domain of instant claim 31; wherein said comprises PD-1 x CTLA-4 bispecific molecule: (I) two of said PD-1 binding domains; and (II) two of said CTLA-4 binding domains of instant claim 33; wherein said PD-1 x CTLA-4 bispecific molecule comprises a hinge domain and an Fc region of an IgG4 subtype of instant claim 35; wherein said Fc Region is a variant Fc Region that comprises: (a) one or more amino acid modifications that reduces the affinity of the variant Fc Region for an FcyR, wherein said modifications comprise the substitution of L234A or L235A, or L234A and L235A, wherein said numbering is that of the EU index as in Kabat; and/or (b) one or more amino acid modifications that enhances the serum half-life of the variant Fc Region, wherein said modifications comprise the substitution of M252Y; or M252Y and S254T; or M252Y and T256E; or M252Y, S254T and T256E; or K288D and H435K, wherein said numbering is that of the EU index as in Kabat of instant claim 36; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose between about 3 mg/kg and 8 mg/kg of instant claim 39; wherein said PD-1 x CTLA-4 bispecific molecule is administered to said subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks during an induction period of instant claim 40; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said induction period of instant claim 41; further comprising administering said PD-1 x CTLA-4 bispecific molecule to said subject at a dose of from about 3 mg/kg to about 10 mg/kg once every 6 weeks during a maintenance period, wherein said maintenance period follows said induction period of instant claim 43; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said maintenance period of instant claim 44; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of about 6 mg/kg during said maintenance period of instant claim 45; further comprising administering a therapeutically of prophylactically effective amount of one or more additional therapeutic agents or chemotherapeutic agents of instant claim 49; a method of stimulating immune cells comprising administering a PD-1 x CTLA-4 bispecific molecule wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 Binding Domain and a CTLA-4 Binding Domain, and wherein said method comprises administering said PD-1 x CTLA-4 bispecific molecule to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks of instant claim 51; and a pharmaceutical kit comprising a container comprising a PD-1 x CTLA-4 bispecific molecule of instant claim 53.
The claims encompass a broad genus of PD-1 x CTLA-4 bispecific molecules including PD-1 x CTLA bispecific molecules with one or two PD-1 and one or two CTLA-4 binding domains. The skilled artisan cannot envision all the antibody and kit possibilities recited in the instant claims.
Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
The specification must set forth the structural features that allow one of ordinary skill in the art to identify and produce the recited antibodies. In the instant case, definition by function does not suffice to define the genus because it is only an indication of what the antibodies do, rather than what they are.
It is well established in the art that it is highly unpredictable which changes in amino acid sequence can be made in complementarity determining regions (CDRs) of a parental antibody such that the derived antibody retains the binding specificity and affinity of the parent antibody. The art of Mariuzza et al. (PTO-892; page 1, Reference X) reviews the structural basis of antigen-antibody recognition and teaches that a naturally occurring antibody comprises light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure, which fully comprises six "complementarity-determining regions" (CDRs), three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of antibody's antigen-binding specificity. Of the amino acid residues of the antibody contacting the antigen, six are within the light chain, nine are within the heavy chain, and two are within the constant or nearly constant "framework" regions (In particular, whole document). As such, one of skill in the art would not know which of the recited antibody variants would have the claimed function of binding to PD-1 and CTLA-4 because it is the 6 CDRs together which determine the antibody's antigen-binding specificity.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum, et al. (PT0-892; page 1, Reference W) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non- contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis, et al. (PTO-892; page 1, Reference U) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column). Thus, it is unpredictable as to what amino acids can be changed in the original intact antibodies disclosed in the specification wherein the antibodies would still function. Thus, the skilled artisan cannot envision the detailed structure of the encompassed invention and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function.
As evidenced by the art of Goel et al. (PTO-892; page 1, Reference V), Khan et al. (PTO-892; Page 2, Reference U) and Poosarla et al. (PTO-892; Page 2; Reference V), antibody specificity for a particular antigen does not correlate with any particular structure for the antibodies themselves. It was well known to those skilled in the art at the time the invention was made that minor structural differences among structurally related antibodies or compositions thereof could result in substantially different binding activities. Given the lack of guidance in the specification, it is unpredictable which antibodies with which structures would exhibit the recited functions. The specification does not describe a correlation between the structure of the antibodies themselves and their function of binding PD-1 and CTLA-4 such that a skilled artisan would have known what antibody structures possess the claimed functions of treating cancer and stimulating immune cells. The additional recitations wherein said PD-1 x CTLA-4 bispecific molecule comprises (I) two of said PD-1 binding domains and (II) two of said CTLA-4 binding domains of instant claim 33 and wherein said PD-1 x CTLA-4 bispecific molecule comprises a hinge domain and an Fc region of instant claim 35 and wherein said Fc region is a variant Fc region of instant claim 36 do not overcome the lack of correlation between the structure of the antibodies and their recited functions.
The specification does not describe a correlation between the antibody structure and the function of binding PD-1 and CTLA-4 and treating cancer and stimulating immune cells such that a skilled artisan would have known what antibody variants possess the claimed function. "Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features" Ex parte Kubin (83 U.S.P.Q.2d 1410 (BPAI 2007)), at page 16. In this instant case, Applicants have not provided the requisite identifying structural features of the antibodies encompassed. "Without a correlation between structure and function, the claim does little more than define the claimed invention by function" supra, at page 17.
U.S. Court of Appeals for the Federal Circuit recently decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § l 12(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO- issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § l 12(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. , the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id.
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the ... claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 U.S.P.Q.2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed invention. regarding description of the claimed invention, the specification does not provide an adequate written description of the invention claimed herein. See The Regents of the University of California v. Eli Lilly and Company, 43 USPQ2d 1398, 1404-7 (Fed. Cir. 1997). In University of California v. Eli Lilly and Co., 39 U.S.P.Q.2d 1225 (Fed. Cir. 1995) the inventors claimed a genus of DNA species encoding insulin in different vertebrates or mammals, but had only described a single species of cDNA which encoded rat insulin. The court held that only the nucleic acids species described in the specification (i.e. nucleic acids encoding rat insulin) met the description requirement and that the inventors were not entitled to a claim encompassing a genus of nucleic acids encoding insulin from other vertebrates, mammals or humans, id. at 1240. The Federal Circuit has held that if an inventor is "unable to envision the detailed constitution of a gene so as to distinguish it from other materials . . . conception has not been achieved until reduction to practice has occurred", Amgen, Inc. v. Chugai Pharmaceutical Co, Ltd., 18 U.S.P.Q.2d 016 (Fed. Cir. 1991). Attention is also directed to the decision of The Regents of the University of California v. Eli Lilly and Company (CAFC, July 1997) wherein is stated: "The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 222 USPQ 369, 372-373 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[ e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, as we have previously held, a cDNA is not defined or described by the mere name "cDNA," even if accompanied by the name of the protein that it encodes, but requires a kind of specificity usually achieved by means of the recitation of the sequence of nucleotides that make up the cDNA." See Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606.
As such, there is insufficient written description of the required kind of structure identifying information about the corresponding makeup of the claimed antibodies to
demonstrate possession.
Enablement
Claims 31-47 and 49-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While being enabled for: a method of treating ovarian cancer and clear cell carcinoma comprising administering a PD-1 x CTLA-4 bispecific molecule with a VHPD-1 of SEQ ID NO:5 comprising CDRH1, 2, and 3 with SEQ ID NOs:6, 7, and 8, respectively, and a VLPD-1 of SEQ ID NO:1 comprising CDRL1, 2, and 3 with SEQ ID NOs:2, 3, and 4, respectively; and a VHCTLA-4 of SEQ ID NO:13 comprising CDRH1, 2, and 3 with SEQ ID NOs:14, 15, and 16, respectively, and a VLCTLA-4 of SEQ ID NO:9 comprising CDRL1, 2, and 3 with SEQ ID NOs:10, 11, and 12, respectively; wherein, the bispecific molecule contains two polypeptide chains of SEQ ID NO:40 and two polypeptide chains of SEQ ID NO:41; a method of stimulating T cells comprising a PD-1 x CTLA-4 bispecific molecule with a VHPD-1 of SEQ ID NO:5 comprising CDRH1, 2, and 3 with SEQ ID NOs:6, 7, and 8, respectively, and a VLPD-1 of SEQ ID NO:1 comprising CDRL1, 2, and 3 with SEQ ID NOs:2, 3, and 4, respectively; and a VHCTLA-4 of SEQ ID NO:13 comprising CDRH1, 2, and 3 with SEQ ID NOs:14, 15, and 16, respectively, and a VLCTLA-4 of SEQ ID NO:9 comprising CDRL1, 2, and 3 with SEQ ID NOs:10, 11, and 12, respectively; wherein, the bispecific molecule contains two polypeptide chains of SEQ ID NO:40 and two polypeptide chains of SEQ ID NO:41;
The specification does not reasonably provide enablement for: a method of treating cancer comprising administering a PD-1 x CTLA-4 bispecific molecule wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 binding domain and a CTLA-4 binding domain of instant claim 31; wherein said comprises PD-1 x CTLA-4 bispecific molecule: (I) two of said PD-1 binding domains; and (II) two of said CTLA-4 binding domains of instant claim 33; wherein said PD-1 x CTLA-4 bispecific molecule comprises a hinge domain and an Fc region of an IgG1, IgG2, IgG3, or IgG4 isotype of instant claim 35; wherein said Fc region is a variant Fc region that comprises: (a) one or more amino acid modifications that reduces the affinity of the variant Fc Region for an FcyR, wherein said modifications comprise the substitution of L234A or L235A, or L234A and L235A, wherein said numbering is that of the EU index as in Kabat; and/or (b) one or more amino acid modifications that enhances the serum half-life of the variant Fc Region, wherein said modifications comprise the substitution of M252Y; or M252Y and S254T; or M252Y and T256E; or M252Y, S254T and T256E; or K288D and H435K, wherein said numbering is that of the EU index as in Kabat of instant claim 36; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose between about 3 mg/kg and 8 mg/kg of instant claim 39; wherein said PD-1 x CTLA-4 bispecific molecule is administered to said subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks during an induction period of instant claim 40; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said induction period of instant claim 41; further comprising administering said PD-1 x CTLA-4 bispecific molecule to said subject at a dose of from about 3 mg/kg to about 10 mg/kg once every 6 weeks during a maintenance period, wherein said maintenance period follows said induction period of instant claim 43; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said maintenance period of instant claim 44; wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of about 6 mg/kg during said maintenance period of instant claim 45; further comprising administering a therapeutically of prophylactically effective amount of one or more additional therapeutic agents or chemotherapeutic agents of instant claim 49; a method of stimulating immune cells comprising administering a PD-1 x CTLA-4 bispecific molecule wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 Binding Domain and a CTLA-4 Binding Domain, and wherein said method comprises administering said PD-1 x CTLA-4 bispecific molecule to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks of instant claim 51; and a pharmaceutical kit comprising a container comprising a PD-1 x CTLA-4 bispecific molecule of instant claim 53.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The breadth of claims 31-47 and 49-53 encompass methods of treating any cancer with any PD-1 x CTLA-4 bispecific molecule (including PD-1 x CTLA-4 bispecific molecules with one or two PD-1 binding domains and one or two CTLA-4 binding domains AND PD-1 x CTLA-4 bispecific molecules with variant Fc regions) with any additional therapeutic agent or chemotherapeutic agent. Cancer has different causes, affect different physiological processes, and are treated with different agents. The breadth of claim 53 encompasses pharmaceutical kits with any PD-1 x CTLA-4 bispecific molecule.
The specification (Example 3) describes a dose escalation Phase I clinical study to study the tolerability of PD-1 x CTLA-4 bispecific molecule, DART-D, in patients with NSCLC, SCCHN, RCC, cervical cancer, soft tissue sarcoma, and CRC. Objective responses were observed in 4 patients and 9 patients had stable disease. DART-D administration was associated with enhanced proliferation of peripheral CD8+ T cells, but no associated changes in Treg population.
Klein-Brill et al (PTO-892; page 3, Reference U; “KB”) teaches that combined CTAL-4 and PD-1 blockade is most beneficial for patients with multi-organ metastasis while those with oligo-organ metastasis fare better with PD-1 monotherapy due to intra- and inter-tumoral heterogeneity and differences in immune system responses (KB; Abstract; page 6, right column, paragraphs 1-3). Li et al (PTO-892; page 3, Reference V; “Li”) teaches even in ovarian cancer there are marked differences in the therapeutic benefits with PD-1 x CTLA-4 bispecific molecule therapy between different histological subtypes due to tumor heterogeneity and immunosuppressive tumor immune microenvironment (Li; Abstract; Section 6.1-6.2).
However, the specification is not enabled for making and using a “PD-1 x CTLA-4 bispecific molecule” to treat a genus of cancer. The specification has not adequately disclosed the genus of this molecule which can be made and used commensurate in scope with the specification for use in a method of treating cancer including ovarian cancer and clear cell carcinoma in combination with additional therapeutic agents or chemotherapeutic agents.
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claim 31 of any as such, not any cancer can be treated effectively with any PD-1 x CTLA-4 bispecific molecule with any additional therapeutic or chemo-therapeutic agent without undue experimentation.
The breadth of claims 51-52 encompasses methods of stimulating any immune cell with any PD-1 x CTLA-4 bispecific molecule.
The specification (Example 3) discloses a dose escalation Phase I clinical study to study the tolerability of PD-1 x CTLA-4 bispecific molecule, DART-D, in patients with NSCLC, SCCHN, RCC, cervical cancer, soft tissue sarcoma, and CRC. Objective responses were observed in 4 patients and 9 patients had stable disease. DART-D administration was associated with enhanced proliferation of peripheral CD8+ T cells, but no associated changes in Treg population.
Curran et al (PTO-892; page 2, Reference X; “Curran”) teaches both CTLA-4 and PD-1 blockade strongly increased infiltration of CD8+ T cells and increased absolute number of infiltrating CD4+ T effector cells (Curran; page 4276, left column, paragraph 4). Seidel et al (PTO-892; page 3, Reference W; “Seidel”) teaches inhibiting the PD-1/PD-L1 pathway may also have T cell-independent effects since other cell types such as dendritic cells and B cells are influenced by PD-1 signaling (Seidel; page 7, left column, paragraph 3; Figure 2).
However, the specification is not enabled for making and using a “PD-1 x CTLA-4 bispecific molecule” to stimulate the genus of immune cells. The specification has not adequately disclosed the genus of this molecule which can be made and used commensurate in scope with the specification for use in a method stimulating immune cells.
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claim 31 of any as such, not any immune cell can be stimulated with any PD-1 x CTLA-4 bispecific without undue experimentation.
In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability in the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed PD-1 x CTLA-4 bispecific molecule to treat ovarian cancer and clear cell carcinoma with any additional therapeutic agent or chemotherapeutic agent and stimulate the genus of immune cells.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Priority
This application is a 371 of PCT/US2021/042901 effectively filed on 07/23/2021 which claims domestic priority to U.S. Provisional Application 63/057,054 effectively filed on 7/27/2020, U.S. Provisional Application 63/177,036 effectively filed on 4/20/2021, and U.S. Provisional Application 63/219,066 effectively filed on 7/7/2021.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 31-39, 47, and 49-53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication 2019/0161548 A1 (IDS filed on 8/30/2023; Reference US20; "Johnson").
Johnson teaches methods of treating cancer including ovarian cancer and clear cell carcinoma comprising administering bispecific molecules including diabodies and bispecific antibodies that possess at least one polypeptide chain that encodes a heavy chain variable domain (VH) and a light chain variable domain (VL) that binds PD-1 and CTLA-4 that can be used to stimulate an immune response (Johnson; Abstract; [0003]; [0024]-[0029]; [0378]-[0380]). Johnson teaches that there is a need to improve compositions capable of more vigorously directing the body’s immune system to attack cancer cells, especially to lower therapeutic concentrations and/or with reduced side effects and targeting both PD-1 and CTLA-4 promotes the activation and continued activation of the immune system (Johnson; [0020]-[0021]). The PD-1 x CTLA-4 bispecific antibodies (DART A, B, C, D, E) exhibits an activity that is enhanced relative to such activity exhibited by two monospecific molecules that possess the VH and VLs of the antibody that binds PD-1 and CTLA-4 and the molecule elicits fewer immune-related adverse events when compared to the administration of a CTLA-4 monospecific antibody, ipilimumab (Johnson; [0029]-[0030]; Example 1; Example 5-6; Table 9). Johnson teaches the bispecific antibody is administered to patients with cancer including ovarian cancer and clear cell carcinoma at a therapeutically effective amount which is between 0.01 ug/kg to 150 mg/kg where the dosage is preferably determined based on the patient’s body weight and while individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art (Johnson; [0379]-[0380]; [0393]-[0395]). Additionally, Johnson teaches administration of the bispecific antibody can be administered once every two weeks to once a month and that effective dosage of the molecules used for treatment may increase or decrease over the course of a particular treatment (Johnson; [0400]). In particular, DART D, when administered to a murine model with GVHD, markedly enhanced T cell proliferation (both T cell counts and expression of Ki-67), increased lymphocyte count, increased globulin levels, and increased spleen and thymus organ weights (Johnson; [0593]).
Regarding instant claim 31, Johnson teaches a method of treating a cancer comprising administering a PD-1 x CTLA-4 bispecific molecule to a subject in need thereof, wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 Binding Domain and a CTLA-4 Binding Domain, and wherein said method comprises administering said PD-1 x CTLA-4 bispecific molecule to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks (Johnson; [0020]-[0021]; [0378]-[380]; [0593]; Examples 1, 5-6; Table 9).
Regarding instant claim 32, Johnson teaches wherein said PD-1 binding domain comprises a VLPD-1 that comprises the CDRL1, 2, 3 of SEQ ID NO:1, and a VHPD-1 that comprises the CDRH1, 2, 3 of SEQ ID NO:5; and a CTLA-4 binding domain comprises a VLCTLA-4 that comprises the CDRL1, 2, 3 of SEQ ID NO:9, and a VHCTLA-4 that comprises the CDRH1, 2, 3 of SEQ ID NO:13 (Reference antibody, DART D, comprises a first and third polypeptide chain of reference SEQ ID NO:99 which comprises 100% sequence identity to instant VLPD-1 CDRL1, 2, and 3 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 CDRH1, 2, and 3 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:100 which comprises 100% sequence identity to instant VLCTLA-4 CDRL1, 2, and 3 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 CDRH1, 2, and 3 (instant SEQ ID NO:5) between reference amino acids 117-235) (Reference antibody, DART C, comprises a first and third polypeptide chain of reference SEQ ID NO:97 which comprises 100% sequence identity instant VLPD-1 CDRL1, 2, and 3 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 CDRH1, 2, and 3 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:98 which comprises 100% sequence identity to instant VLCTLA-4 CDRL1, 2, and 3 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 CDRH1, 2, and 3 (instant SEQ ID NO:5) between reference amino acids 117-235) (Johnson; [0324]-[0333]; Table 9; Figure 3C).
Regarding instant claim 33, Johnson teaches wherein said PD-1 x CTLA-4 bispecific molecule comprises: (I) two of said PD-1 Binding Domains; and (II) two of said CTLA-4 Binding Domains (Johnson; [0324]-[0333]; Table 9; Figure 3C).
Regarding instant claim 34, Johnson teaches wherein (a) said PD-1 Binding Domain comprises the VL Domain of SEQ ID NO:1 and the VH Domain of SEQ ID NO:5; and (b) said CTLA-4 Binding Domain comprises the VL Domain of SEQ ID NO:9 and the VH Domain of SEQ ID NO:13 (Reference antibody, DART D, comprises a first and third polypeptide chain of reference SEQ ID NO:99 which comprises 100% sequence identity to instant VLPD-1 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:100 which comprises 100% sequence identity to instant VLCTLA-4 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 (instant SEQ ID NO:5) between reference amino acids 117-235) (Reference antibody, DART C, comprises a first and third polypeptide chain of reference SEQ ID NO:97 which comprises 100% sequence identity instant VLPD-1 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:98 which comprises 100% sequence identity to instant VLCTLA-4 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 (instant SEQ ID NO:5) between reference amino acids 117-235) (Johnson; [0324]-[0333]; Table 9; Figure 3C).
Regarding instant claim 35, Johnson teaches wherein said PD-1 x CTLA-4 bispecific molecule comprises a Hinge Domain and an Fc Region of an IgG 1, IgG2, IgG3, or IgG4 isotype (Johnson; [0169]; [0193]; [0324]-[0333]).
Regarding instant claim 36, Johnson teaches wherein said Fc Region is a variant Fc Region that comprises: (a) one or more amino acid modifications that reduces the affinity of the variant region for an FcγR; and/or (b) one or more amino acid modifications that enhances the serum half-life of the variant Fc Region, wherein said modifications comprise the substitution M252Y, S254T and T256E wherein said numbering is that of the EU index as in Kabat (Johnson; [0031]-[0032]; [0035]; [0277]; [0329]-[0335]).
Regarding instant claim 37, Johnson teaches wherein said PD-1 x CTLA-4 bispecific molecule is a diabody comprising one polypeptide chain that comprises the amino acid sequence of SEQ ID NO:40 and a second polypeptide chain that comprises the amino acid sequence of SEQ ID NO:41 (Reference antibody, DART D, comprises reference SEQ ID NO: 99 which is 100% sequence identical to instant SEQ ID NO:40; AND comprises reference SEQ ID NO:100 which is 100% sequence identical to instant SEQ ID NO:41) (Johnson; [0329]-[0333]; Table 9; Figure 3C).
Regarding instant claim 38, Johnson teaches wherein said PD-1 x CTLA-4 bispecific molecule is a diabody comprising two polypeptide chains each comprising the amino acid sequence of SEQ ID NO:40 and two polypeptide chains each comprising the amino acid sequence of SEQ ID NO:41 (Reference antibody, DART D, comprises reference SEQ ID NO: 99 which is 100% sequence identical to instant SEQ ID NO:40; AND comprises reference SEQ ID NO:100 which is 100% sequence identical to instant SEQ ID NO:41) (Johnson; [0329]-[0333]; Table 9; Figure 3C).
Regarding instant claim 39, Johnson teaches wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg (Johnson; [0394]; [0400]).
Regarding instant claim 47, Johnson teaches wherein said cancer is ovarian cancer or clear cell carcinoma (Johnson; [0379]-[0380]).
Regarding instant claim 49, Johnson teaches the method of claim 31 further comprising administering a therapeutically or prophylactically effective amount of one additional therapeutic agents or chemotherapeutic agents (Johnson; [0396]).
Regarding instant claim 50, Johnson teaches wherein said subject in need thereof is a human (Johnson; Abstract; [0386]).
Regarding claim 51, Johnson teaches a method of stimulating immune cells comprising administering a PD-1 x CTLA-4 bispecific molecule to a subject in need thereof, wherein said PD-1 x CTLA-4 bispecific molecule comprises a PD-1 Binding Domain and a CTLA-4 Binding Domain, and wherein said method comprises administering said PD-1 x CTLA-4 bispecific molecule to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks (Johnson; [0379]-[0380]).
Regarding claim 52, Johnson teaches wherein said immune cells are T cells (Johnson; [0378]; [0542]-[0549]).
Regarding claim 53, Johnson teaches a pharmaceutical kit comprising: (a) a container comprising a PD-1 x CTLA-4 bispecific molecule; and (b) an instructional material, wherein the instructional material instructs that said PD-1 x CTLA-4 bispecific molecule is to be used according to the method of claim 31 (Johnson; [0378]; [0384]-[0385]).
The reference teachings anticipate the claimed invention.
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.
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 31 and 40-46 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2019/0161548 A1 (IDS filed on 8/30/2023; IDS Reference US20; "Johnson") in view of WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") and WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”).
Johnson has been discussed above. Johnson differs from the claimed invention in regards to instant claim 40 wherein said PD-1 x CTLA-4 bispecific molecule is administered to said subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks during an induction period; instant claim 41 wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said induction period; instant claim 42 wherein said induction period has a duration of up to about 24 weeks; instant claim 43 wherein the method of claim 40 further comprising administering said PD-1 x CTLA-4 bispecific molecule to said subject at a dose of from about 3 mg/kg to about 10 mg/kg once every 6 weeks during a maintenance period, wherein said maintenance period follows said induction period; instant claim 44 wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of between about 3 mg/kg and 8 mg/kg during said maintenance period; instant claim 45 wherein said PD-1 x CTLA-4 bispecific molecule is administered at a dose of about 6 mg/kg during said maintenance period; and instant claim 46 wherein said maintenance period has a duration of up to about 84 weeks.
However, Cogswell does teach combination treatment for patients with cancer using anti-PD-1 and anti-CTLA-4 antibodies (Cogswell; Abstract; page 10, lines 15-18). Cogswell teaches a preferred concurrent dosing regimen to include an induction dosing schedule comprising combined administration of the anti-PD-I and anti-CTLA-4 Abs at a dosing frequency of once every 3 weeks for at least 2, 4, 6, 8, or 12 doses; followed by (ii) a maintenance dosing schedule comprising combined administration of the anti-PD- I and anti-CTLA-4 antibodies at a dosing frequency of once every 2 to 12 or more weeks for up to 8 doses, or for as long as clinical benefit is observed, or until unmanageable toxicity or disease progression occurs (Cogswell; page 58, lines 24-30; page 62, lines 10-20; Example 4; Example 15). The dosing regimens are adjusted to provide optimum desired response i.e. therapeutic response or minimal adverse effects (Cogswell; page 36, lines 28-29). Cogswell additionally teaches a clinical trial design studying the efficacy of combination anti-PD-1 and anti-CTLA-4 in MEL patients where 21 of 52 patients achieved objective responses, 16 patients had ≥ 80% tumor reduction at 12 weeks including 5 complete responses and overall evidence of clinical activity was observed in 65% of patients (Cogswell; page 127-128; Table 10; Figures 14A and 15-17; Example 17).
Hickingbottom teaches methods of improving delivery of a PD-1 x CTLA-4 bispecific antibody, Xmab20717, to human subjects who possess cancer (Hickingbottom; Abstract; [0014]). Hickingbottom teaches dual checkpoint targeting is a better way to suppress both checkpoint pathways and more specifically targets CTLA4/PD-1 double positive cells that appear critical to re-establishing an anti-tumor immune response (Hickingbottom; [0013]). Hickingbottom teaches Xmab20717 is administered once between about 12 and about 17 days with a preferred embodiment being once every 15 days at a dose between 0.05 mg/kg to 12 mg/kg (Hickingbottom; [0109]; [0114]). Hickingbottom teaches a clinical trial design with a dosing schedule to include 2 doses in each 28-day cycle on Days 1 and 15 with 6 dose levels of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg where Xmab20717 was generally well tolerated where patients exhibited a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Hickingbottom; Example 1, [0146]-0151]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the method of treating cancer comprising administering a PD-1 x CTLA-4 bispecific molecule of Johnson with the dosing regimen (once every 3 weeks) including the induction and maintenance dosing schedule of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer the PD-1 x CTLA-4 bispecific molecule of Johnson with the induction and maintenance dosing schedule of Cogswell so that patients with cancer can achieve their maximum clinical benefit including reducing in tumor size and an increase in clinical activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of treating cancer comprising administering a PD-1 x CTLA-4 bispecific molecule of Johnson with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the method of treating cancer comprising administering a PD-1 x CTLA-4 bispecific molecule of Johnson with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom since Johnson teaches patients treated with PD-1 x CTLA-4 bispecific antibody, DART D, demonstrate good clinical responses and induction of an immune response. Cogswell teaches patients clinical benefit from the administration of anti-PD-1 and anti-CTLA-4 antibodies for an induction period and maintenance period and Hickingbottom teaches dual PD-1 x CTLA-4 targeting is a better way to suppress the checkpoint pathways and doses between 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg were well tolerated by patients where they exhibited a burst of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines. Therefore, a person of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispeciifc antibody of Johnson with the dosing regimen schedule of Cogswell with the doses of Xmab27017 of Hickingbottom to yield predictable results of increasing the clinical efficacy of the PD-1 x CTLA-4 bispecific antibody by enhancing CD4+ and CD8+ T cell response.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
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 31-47 and 49-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-5 of U.S. Patent No. 10,954,301 B2 (PTO-892; Reference A; “’301”) in view of WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”).
‘301 teaches in reference claim 1 a bispecific molecule comprising two polypeptide chains each comprising the polypeptide of SEQ ID NO:99 and two polypeptide chains each comprising the polypeptide of SEQ ID NO:100; in reference claim 3 a bispecific molecule comprising one polypeptide chain comprising SEQ ID NO:104, one polypeptide chain comprising SEQ ID NO:105, one polypeptide chain comprising SEQ ID NO:106, and one polypeptide chain comprising SEQ ID NO:107; in reference claim 4 a bispecific molecule comprising two polypeptide chains each comprising the polypeptide of SEQ ID NO:101 and two polypeptide chains each comprising the polypeptide of SEQ ID NO:100; in reference claim 5 a bispecific molecule comprising one polypeptide chain comprising SEQ ID NO:108, one polypeptide chain comprising SEQ ID NO:105, one polypeptide chain comprising SEQ ID NO:109, and one polypeptide chain comprising SEQ ID NO:107 (Reference SEQ ID NO:100 is 100% sequence identical to instant SEQ ID NO:41 which further comprises 100% sequence identity to instant SEQ ID NO:5 (instant VHPD-1 comprising CDRH1, 2, and 3) between reference amino acids 117-235 and to instant SEQ ID NO:9 (instant VLCTLA-4 comprising CDRL1, 2, and 3) between reference amino acids 1-111. Reference SEQ ID NO:99 is 100% sequence identical to instant SEQ ID NO:40 which further comprises 100% sequence identity to instant SEQ ID NO:1 (instant VLPD-1 comprising CDRL1, 2, and 3) between reference amino acids 1-111 and instant SEQ ID NO:13 (instant VHCTLA-4 comprising CDRH1, 2, and 3) between reference amino acids 120-237).
‘301 does not teach the limitation of instant claim 31 a method of treating a cancer comprising administering a PD-1 x CTLA-4 bispecific antibody to a subject in need thereof wherein said method comprises administering said PD-1 x CTLA-4 bispecific antibody to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks; the dosing regimen and doses of instant claims 39-46 and 49; wherein the cancer is clear cell carcinoma and ovarian cancer of instant claim 47. ‘301 additionally does not teach the limitation of instant claim 51 a method of stimulating immune cells comprising administering a PD-1 x CTLA-4 bispecific molecule wherein said method comprises administering said PD-1 x CTLA-4 bispecific antibody to a subject at a dose of about 3 mg/kg to about 10 mg/kg once every 3 weeks; wherein said immune cells are T cells of instant claim 52. ‘301 does not teach a pharmaceutical kit of instant claim 53.
However, Cogswell does teach combination treatment for patients with ovarian cancer using anti-PD-1 and anti-CTLA-4 antibodies to potentiate an endogenous immune response either stimulating the activation of the endogenous response or inhibiting the suppression of the endogenous response (Cogswell; Abstract; page 10, lines 1-4, 15-18; page 39, lines 9-12; page 60, lines 9-34; Example 3). Cogswell teaches a preferred concurrent dosing regimen to include an induction dosing schedule comprising combined administration of the anti-PD-I and anti-CTLA-4 Abs at a dosing frequency of once every 3 weeks for at least 2, 4, 6, 8, or 12 doses; followed by (ii) a maintenance dosing schedule comprising combined administration of the anti-PD- I and anti-CTLA-4 antibodies at a dosing frequency of once every 2 to 12 or more weeks for up to 8 doses, or for as long as clinical benefit is observed, or until unmanageable toxicity or disease progression occurs (Cogswell; page 58, lines 24-30; page 62, lines 10-20; Example 4; Example 15). The dosing regimens are adjusted to provide optimum desired response i.e. therapeutic response or minimal adverse effects (Cogswell; page 36, lines 28-29). The treatment can be combined with effectively combined with standard cancer treatments including chemotherapy, radiation, surgery, or hormone deprivation in order to increase cancer cell death to increase the levels of tumor antigen in the antigen presentation pathway (Cogswell; page 63, lines 25-34). Cogswell additionally teaches a clinical trial design studying the efficacy of combination anti-PD-1 and anti-CTLA-4 in MEL patients where 21 of 52 patients achieved objective responses, 16 patients had ≥ 80% tumor reduction at 12 weeks including 5 complete responses and overall evidence of clinical activity was observed in 65% of patients (Cogswell; page 127-128; Table 10; Figures 14A and 15-17; Example 17). Cogswell additionally teaches a pharmaceutical kit comprising the anti-PD-1 and anti-CTLA-4 antibodies including instructions for the intended use of the contents (Cogswell; page 72, lines 31-33; page 72, lines 1-9).
Hickingbottom teaches methods of improving delivery of a PD-1 x CTLA-4 bispecific antibody, Xmab20717, to human subjects who possess cancer (Hickingbottom; Abstract; [0014]). Hickingbottom teaches dual checkpoint targeting is a better way to suppress both checkpoint pathways and more specifically targets CTLA-4/PD-1 double positive cells that appear critical to re-establishing an anti-tumor immune response (Hickingbottom; [0013]). Hickingbottom teaches Xmab20717 is administered once between about 12 and about 17 days with a preferred embodiment being once every 15 days at a dose between 0.05 mg/kg to 12 mg/kg (Hickingbottom; [0109]; [0114]). Hickingbottom teaches a clinical trial design with a dosing schedule to include 2 doses in each 28-day cycle on Days 1 and 15 with 6 dose levels of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg where Xmab20717 was generally well tolerated where patients exhibited a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Hickingbottom; Example 1, [0146]-0151]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the PD-1 x CTLA-4 bispecific antibodies of ‘301 with the method of treating patients with ovarian cancer and stimulating immune cells (i.e. T cells) by administering the antibody once every 3 weeks of Cogswell with the specific doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to use the PD-1 x CTLA-4 bispecific antibody of ‘301 in the recited dosing regimens of Cogswell and Hickingbottom in order to effectively treat a patient with ovarian and clear cell carcinoma and enhance the proliferation of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the PD-1 x CTLA-4 bispecific molecule of ‘301 with the dosing regimen (once every 3 weeks) including the induction and maintenance dosing schedule of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer the PD-1 x CTLA-4 bispecific molecule of ‘301 with the induction and maintenance dosing schedule of Cogswell so that patients with cancer can achieve their maximum clinical benefit including reducing in tumor size and an increase in clinical activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the PD-1 x CTLA-4 bispecific molecule of ‘301 with the dosing regimen schedule including the induction and maintenance period of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘301 with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom since Cogswell teaches patients clinical benefit from the administration of anti-PD-1 and anti-CTLA-4 antibodies for an induction period and maintenance period and Hickingbottom teaches dual PD-1 x CTLA-4 targeting is a better way to suppress the checkpoint pathways and doses between 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg were well tolerated by patients where they exhibited a burst of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines. Therefore, a person of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific antibody of ‘301 with the dosing regimen schedule of Cogswell with the doses of Xmab27017 of Hickingbottom to yield predictable results of increasing the clinical efficacy of the PD-1 x CTLA-4 bispecific antibody by enhancing CD4+ and CD8+ T cell response.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the PD-1 x CTLA-4 bispecific molecule of ‘301 with the pharmaceutical kit of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated the combine the PD-1 x CTLA-4 bispecific molecule of ‘301 with the pharmaceutical kit of Cogswell in order to effectively deliver the bispecific molecule to a patient with specific instructions for its intended use.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 31-47 and 49-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, and 11 of U.S. Patent No. 9,856,320 B2 (PTO-892; Reference C; “’320”) in view of US Patent Application Publication 2019/0161548 A1 (IDS filed on 8/30/2023; Reference US20; "Johnson").
‘320 teaches a method of treating a human subject afflicted with a cancer comprising administering (a) an antigen that specifically binds to PD-1; (b) an antibody that specifically binds to CTLA-4; (i) an induction dosing schedule comprising administering the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 2, 3, or 4 weeks, for 2, 4, 6, 8, or 10 doses, followed by; (ii) a maintenance dosing schedule comprising administration of the anti-PD-1 antibody and anti-CTLA-4 antibody at a dosing frequency of once every 8, 12, or 16 weeks, or once a quarter, for 4, 6, 8, 12, or 16 doses at the following dosages of reference claim 1; the wherein the administering comprises (i) an induction dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 3 weeks for 4 doses, followed by administration of the anti-PD-1 antibody alone at a dosing frequency of once every 3 weeks for 4 doses; followed by (ii) a maintenance dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 2 to 12 weeks for up to 8 doses of instant claim 6; wherein the cancer is ovarian cancer of reference claim 8; wherein the treatment is further combined with one or more of chemotherapy, radiation, surgery, hormone deprivation, angiogenesis inhibitors, and an anti-PD-L1 antibody or antigen binding portion thereof of instant claim 11.
‘320 does not teach the specific polypeptide chains of the instant PD-1 x CTLA-4 bispecific molecule of instant claims 32-38 or a pharmaceutical kit comprising (a) a container comprising a PD-1 x CTLA-4 bispecific molecule and (b) an instructional material of instant claim 53.
However, Johnson teaches bispecific molecules including diabodies and bispecific antibodies that possess at least one polypeptide chain that encodes a heavy chain variable domain (VH) and a light chain variable domain (VL) that binds PD-1 and CTLA-4 that can be used in the treatment of cancer and be used to stimulate an immune response (Johnson; Abstract; [0003]; [0024]-[0029]). Johnson teaches that there is a need to improve compositions capable of more vigorously directing the body’s immune system to attack cancer cells, especially to lower therapeutic concentrations and/or with reduced side effects and targeting both PD-1 and CTLA-4 promotes the activation and continued activation of the immune system (Johnson; [0020]-[0021]). The proposed PD-1 x CTLA-4 bispecific antibodies (DART A, B, C, D, E) exhibits an activity that is enhanced relative to such activity exhibited by two monospecific molecules that possess the VH and VLs of the antibody that binds PD-1 and CTLA-4 and the molecule elicits fewer immune-related adverse events when compared to the administration of a CTLA-4 monospecific antibody, ipilimumab (Johnson; [0029]-[0030]; Example 1; Example 5-6; Table 9). Johnson teaches the bispecific antibody is administered to patients with cancer including ovarian cancer and clear cell carcinoma at a therapeutically effective amount which is between 0.01 ug/kg to 150 mg/kg where the dosage is preferably determined based on the patient’s body weight and while individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art (Johnson; [0379]-[0380]; [0393]-[0395]). Additionally, Johnson teaches administration of the bispecific antibody can be administered once every two weeks to once a month and that effective dosage of the molecules used for treatment may increase or decrease over the course of a particular treatment (Johnson; [0400]). In particular, DART D, when administered to a murine model with GVHD, markedly enhanced T cell proliferation (both T cell counts and expression of Ki-67), increased lymphocyte count, increased globulin levels, and increased spleen and thymus organ weights (Johnson; [0593]). (Reference antibody, DART D, comprises a first and third polypeptide chain of reference SEQ ID NO:99 which comprises 100% sequence identity to instant VLPD-1 CDRL1, 2, and 3 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 CDRH1, 2, and 3 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:100 which comprises 100% sequence identity to instant VLCTLA-4 CDRL1, 2, and 3 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 CDRH1, 2, and 3 (instant SEQ ID NO:5) between reference amino acids 117-235. Reference SEQ ID NO:99 is 100% sequence identical to instant SEQ ID NO:40 and reference SEQ ID NO:100 is 100% sequence identical to instant SEQ ID NO:41) (Reference antibody, DART C, comprises a first and third polypeptide chain of reference SEQ ID NO:97 which comprises 100% sequence identity instant VLPD-1 CDRL1, 2, and 3 (instant SEQ ID NO:1) between reference amino acids 1-111 and 100% sequence identity to instant VHCTLA-4 CDRH1, 2, and 3 (instant SEQ ID NO:13) between reference amino acids 120-237; AND a second and fourth polypeptide chains of reference SEQ ID NO:98 which comprises 100% sequence identity to instant VLCTLA-4 CDRL1, 2, and 3 (instant SEQ ID NO:9) between reference amino acids 1-111 and 100% sequence identity to instant VHPD-1 CDRH1, 2, and 3 (instant SEQ ID NO:5) between reference amino acids 117-235) (Johnson; [0324]-[0333]; Table 9; Figure 3C).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combined the method of treating a human subject afflicted with a cancer in the recited dosing regimen of ‘320 with the bispecific molecules, DARTC- D, of Johnson with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the method of treating a human subject afflicted with cancer in the recited dosing regimen of ‘320 with the bispecific molecules, DART C-D, of Johnson since Johnson teaches a dual targeting bispecific antibody exhibits enhanced activity relative to such activity exhibited by two monospecific molecules that possess the same PD-1 and CTLA-4 VH and VLs and the molecule elicits fewer immune-related adverse events when compared to the administration of a CTLA-4 monospecific antibody, ipilimumab. Therefore, one of ordinary skill in the art would have been motivated to combine the method of ‘320 with DARTs C-D of Johnson to yield predictable results of enhanced activity of the bispecific antibody and fewer side effects.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the method of treating a human subject afflicted with a cancer in the recited dosing regimen of ‘320 with the pharmaceutical kit comprising PD-1 x CTLA-4 bispecific molecule and instructions for use of Johnson with reasonable expectation of success. One of ordinary skill in the art would have been motivated the combine the method of treating a human subject afflicted with a cancer in the recited dosing regimen of ‘320 with the pharmaceutical kit comprising the PD-1 x CTLA-4 bispecific molecule and the instructions for use of Johnson in order to effectively deliver the bispecific molecule to a patient with specific instructions for its intended use.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 31-34, 37-47, and 49-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 11,840,571 B2 (PTO-892; Reference B; “‘571”) in view of WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") and WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”).
‘571 teaches in reference claim 1 a method for treating a disease or condition associated with a suppressed immune system, comprising administering to a subject in need thereof a composition comprising a bispecific molecule in an amount effective to treat the disease or condition, wherein the bispecific molecule comprises two polypeptide chains each comprising the polypeptide of SEQ ID NO:99 and two polypeptide chains each comprising the polypeptide of SEQ ID NO:100; wherein the disease or condition is cancer or an infection in reference claim 2; wherein the cancer is characterized by the presence of a clear cell carcinoma or ovarian cancer of reference claim 3; and a method for stimulating an immune-mediated response, comprising administering to a subject in need thereof a composition comprising a bispecific molecule in an amount effective to stimulate an immune-mediated response, wherein the bispecific molecule comprises two polypeptide chains each comprising the polypeptide of SEQ ID NO:99 and two polypeptide chains each comprising the polypeptide of SEQ ID NO:100 of reference claim 5 (Reference SEQ ID NO:100 is 100% sequence identical to instant SEQ ID NO:41 which further comprises 100% sequence identity to instant SEQ ID NO:5 (instant VHPD-1 CDRH1, 2, and 3) between amino acids 117-235 and to instant SEQ ID NO:9 (instant VLCTLA-4 CDRL1, 2, and 3) between amino acids 1-111. Reference SEQ ID NO:99 is 100% sequence identical to instant SEQ ID NO:40 which further comprises 100% sequence identity to instant SEQ ID NO:1 (instant VLPD-1 CDRL1, 2, and 3) between amino acids 1-111 and instant SEQ ID NO:13 (VHCTLA-4 CDRH1, 2, and 3) between amino acids 120-237).
‘571 does not teach administering the bispecific molecule in the specific dosing regimen of instant claims 39-46 and 51 or a pharmaceutical kit comprising a container comprising the bispecific molecule and instructions for use.
However, Cogswell does teach combination treatment for patients with ovarian cancer using anti-PD-1 and anti-CTLA-4 antibodies to potentiate an endogenous immune response either stimulating the activation of the endogenous response or inhibiting the suppression of the endogenous response (Cogswell; Abstract; page 10, lines 1-4, 15-18; page 39, lines 9-12; page 60, lines 9-34; Example 3). Cogswell teaches a preferred concurrent dosing regimen to include an induction dosing schedule comprising combined administration of the anti-PD-I and anti-CTLA-4 Abs at a dosing frequency of once every 3 weeks for at least 2, 4, 6, 8, or 12 doses; followed by (ii) a maintenance dosing schedule comprising combined administration of the anti-PD- I and anti-CTLA-4 antibodies at a dosing frequency of once every 2 to 12 or more weeks for up to 8 doses, or for as long as clinical benefit is observed, or until unmanageable toxicity or disease progression occurs (Cogswell; page 58, lines 24-30; page 62, lines 10-20; Example 4; Example 15). The dosing regimens are adjusted to provide optimum desired response i.e. therapeutic response or minimal adverse effects (Cogswell; page 36, lines 28-29). The treatment can be combined with effectively combined with standard cancer treatments including chemotherapy, radiation, surgery, or hormone deprivation in order to increase cancer cell death to increase the levels of tumor antigen in the antigen presentation pathway (Cogswell; page 63, lines 25-34). Cogswell additionally teaches a clinical trial design studying the efficacy of combination anti-PD-1 and anti-CTLA-4 in MEL patients where 21 of 52 patients achieved objective responses, 16 patients had ≥ 80% tumor reduction at 12 weeks including 5 complete responses and overall evidence of clinical activity was observed in 65% of patients (Cogswell; page 127-128; Table 10; Figures 14A and 15-17; Example 17). Cogswell additionally teaches a pharmaceutical kit comprising the anti-PD-1 and anti-CTLA-4 antibodies including instructions for the intended use of the contents (Cogswell; page 72, lines 31-33; page 72, lines 1-9).
Hickingbottom teaches methods of improving delivery of a PD-1 x CTLA-4 bispecific antibody, Xmab20717, to human subjects who possess cancer (Hickingbottom; Abstract; [0014]). Hickingbottom teaches dual checkpoint targeting is a better way to suppress both checkpoint pathways and more specifically targets CTLA-4/PD-1 double positive cells that appear critical to re-establishing an anti-tumor immune response (Hickingbottom; [0013]). Hickingbottom teaches Xmab20717 is administered once between about 12 and about 17 days with a preferred embodiment being once every 15 days at a dose between 0.05 mg/kg to 12 mg/kg (Hickingbottom; [0109]; [0114]). Hickingbottom teaches a clinical trial design with a dosing schedule to include 2 doses in each 28-day cycle on Days 1 and 15 with 6 dose levels of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg where Xmab20717 was generally well tolerated where patients exhibited a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Hickingbottom; Example 1, [0146]-0151]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the PD-1 x CTLA-4 bispecific antibodies of ‘571 with the method of treating patients with ovarian cancer and stimulating immune cells (i.e. T cells) by administering the antibody once every 3 weeks of Cogswell with the specific doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to use the PD-1 x CTLA-4 bispecific antibody of ‘571 in the recited dosing regimens of Cogswell and Hickingbottom in order to effectively treat a patient with ovarian and clear cell carcinoma and enhance the proliferation of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen (once every 3 weeks) including the induction and maintenance dosing schedule of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer the PD-1 x CTLA-4 bispecific molecule of ‘571 with the induction and maintenance dosing schedule of Cogswell so that patients with cancer can achieve their maximum clinical benefit including reducing in tumor size and an increase in clinical activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule including the induction and maintenance period of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom since Cogswell teaches patients clinical benefit from the administration of anti-PD-1 and anti-CTLA-4 antibodies for an induction period and maintenance period and Hickingbottom teaches dual PD-1 x CTLA-4 targeting is a better way to suppress the checkpoint pathways and doses between 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg were well tolerated by patients where they exhibited a burst of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines. Therefore, a person of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific antibody of ‘571 with the dosing regimen schedule of Cogswell with the doses of Xmab27017 of Hickingbottom to yield predictable results of increasing the clinical efficacy of the PD-1 x CTLA-4 bispecific antibody by enhancing CD4+ and CD8+ T cell response.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated the combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell in order to effectively deliver the bispecific molecule to a patient with specific instructions for its intended use.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 31 and 35-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 11,840,571 B2 (PTO-892; Reference B; “’571”) and WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") and WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”) as applied above to claims 31-34, 37-47, and 49-53 in further view of US Patent Application Publication 2019/0161548 A1 (IDS filed on 8/30/2023; Reference US20; "Johnson").
‘571, Cogswell, and Hickingbottom have been discussed above. ‘571, Cogswell, and Hickingbottom differ from the claimed invention in regards to instant claim 35 wherein said PD-1 x CTLA-4 bispecific molecule comprises a Hinge Domain and an Fc Region of an IgG 1, IgG2, IgG3, or IgG4 isotype and instant claim 36 wherein said Fc Region is a variant Fc Region that comprises M252Y, S254T and T256E that enhances the serum half-life of the variant Fc Region.
However, Johnson teaches that there is a need to improve compositions capable of more vigorously directing the body’s immune system to attack cancer cells, especially to lower therapeutic concentrations and/or with reduced side effects and targeting both PD-1 and CTLA-4 promotes the activation and continued activation of the immune system (Johnson; [0020]-[0021]). The proposed PD-1 x CTLA-4 bispecific molecule, DART D, when administered to a murine model with GVHD, markedly enhanced T cell proliferation (both T cell counts and expression of Ki-67), increased lymphocyte count, increased globulin levels, and increased spleen and thymus organ weights (Johnson; [0593]). (Reference antibody, DART D, comprises reference SEQ ID NO:100 is 100% sequence identical to instant SEQ ID NO:41 which further comprises 100% sequence identity to instant SEQ ID NO:5 (instant VHPD-1 CDRH1, 2, and 3) between amino acids 117-235 and to instant SEQ ID NO:9 (instant VLCTLA-4 CDRL1, 2, and 3) between amino acids 1-111. Reference SEQ ID NO:99 is 100% sequence identical to instant SEQ ID NO:40 which further comprises 100% sequence identity to instant SEQ ID NO:1 (instant VLPD-1 CDRL1, 2, and 3) between amino acids 1-111 and instant SEQ ID NO:13 (VHCTLA-4 CDRH1, 2, and 3) between amino acids 120-237) (Johnson; [0324]-[0333]; Table 9; Figure 3C). DART D comprises a hinge domain and an IgG4 variant Fc regions with modifications to increase serum half-life of M252Y, S254T, and T256E and modifications that reduces the affinity of the variant FC region for FcγR (Johnson; [0030]-[0032]; [0193]; [0209]; [0227]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to have modified the method of treating a patient with a PD-1 x CTLA-4 bispecific molecule of ‘571 with the hinge region and variant Fc domain of Johnson with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification to yield a predictable result of extending the serum half-life of the bispecific molecule to allow for less frequent dosing and fewer immune related adverse events.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claims 31-36, 39-47, and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-27 and 29-32 of copending Application No. 18/499,658 in view of WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") and WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”).
‘658 teaches a bispecific molecule comprising one or more epitope-binding sites capable of immunospecific binding to an epitope of PD-1 comprising the VH domain of PD-1 mAb 6-I VH (SEQ ID NO:86) and the VL domain of PD-1 mAb 6-SQ (SEQ ID NO:87) and one or more epitope binding sites capable of immunospeciifc binding to an epitope of CTLA-4 comprising the VH domain of CTLA_4 mAb 3 (SEQ ID NO:90) and the VL domain of CTLA-4 mAb 3 (SEQ ID NO:91) of reference claims 21-23 (Reference SEQ ID NO:86 is 100% sequence identical to instant SEQ ID NO:5 (instant VHPD-1 CDRH1, 2, and 3), Reference SEQ ID NO: 87 is 100% sequence identical to instant SEQ ID NO:1 (instant VLPD-1 CDRL1, 2, and 3), Reference SEQ ID NO:90 is 100% sequence identical to instant SEQ ID NO:13 (VHCTLA-4 CDRH1, 2, and 3), and Reference SEQ ID NO:91 is 100% sequence identical to instant SEQ ID NO:9 (instant VLCTLA-4 CDRL1, 2, and 3)); wherein said molecule comprises an Fc region of instant claim 24; wherein said Fc region is a variant Fc region that comprises: (A) one or more amino acid modifications that reduces the affinity of the variant Fc region for an FcγR; and/or (B) one or more amino acid modifications that enhances the serum half-life of the variant Fc region of instant claim 25; wherein said modifications that reduces the affinity of the variant Fc region for an FcγR comprises the substitution of L234A; L235A or L234A and L235A, wherein said numbering is that of the EU index as in Kabat of reference claim 26; wherein said modifications that enhances the serum half-life of the variant Fc region comprise the substitution of M252Y; M252Yand S254T; M252Y and T256E; M252Y, S254T, and T256E; or K288D and H435K, wherein said numbering is that of the EU index as in Kabat of reference claim 27; wherein said molecule is used to promote stimulation of an immune-mediated response of a subject in need thereof of reference claim 29; wherein said molecule is used in the treatment of a disease or condition associated with a suppressed immune system of reference claim 30; wherein the disease of condition is of reference claim 31; and wherein said cancer is a clear cell carcinoma or ovarian cancer of reference claim 32.
‘658 does not teach the specific dosing regimen of the PD-1 x CTLA-4 bispecific molecule of instant claims 31 and 39-46 and the pharmaceutical kit of instant claim 53.
However, Cogswell does teach combination treatment for patients with ovarian cancer using anti-PD-1 and anti-CTLA-4 antibodies to potentiate an endogenous immune response either stimulating the activation of the endogenous response or inhibiting the suppression of the endogenous response (Cogswell; Abstract; page 10, lines 1-4, 15-18; page 39, lines 9-12; page 60, lines 9-34; Example 3). Cogswell teaches a preferred concurrent dosing regimen to include an induction dosing schedule comprising combined administration of the anti-PD-I and anti-CTLA-4 Abs at a dosing frequency of once every 3 weeks for at least 2, 4, 6, 8, or 12 doses; followed by (ii) a maintenance dosing schedule comprising combined administration of the anti-PD- I and anti-CTLA-4 antibodies at a dosing frequency of once every 2 to 12 or more weeks for up to 8 doses, or for as long as clinical benefit is observed, or until unmanageable toxicity or disease progression occurs (Cogswell; page 58, lines 24-30; page 62, lines 10-20; Example 4; Example 15). The dosing regimens are adjusted to provide optimum desired response i.e. therapeutic response or minimal adverse effects (Cogswell; page 36, lines 28-29). The treatment can be combined with effectively combined with standard cancer treatments including chemotherapy, radiation, surgery, or hormone deprivation in order to increase cancer cell death to increase the levels of tumor antigen in the antigen presentation pathway (Cogswell; page 63, lines 25-34). Cogswell additionally teaches a clinical trial design studying the efficacy of combination anti-PD-1 and anti-CTLA-4 in MEL patients where 21 of 52 patients achieved objective responses, 16 patients had ≥ 80% tumor reduction at 12 weeks including 5 complete responses and overall evidence of clinical activity was observed in 65% of patients (Cogswell; page 127-128; Table 10; Figures 14A and 15-17; Example 17). Cogswell additionally teaches a pharmaceutical kit comprising the anti-PD-1 and anti-CTLA-4 antibodies including instructions for the intended use of the contents (Cogswell; page 72, lines 31-33; page 72, lines 1-9).
Hickingbottom teaches methods of improving delivery of a PD-1 x CTLA-4 bispecific antibody, Xmab20717, to human subjects who possess cancer (Hickingbottom; Abstract; [0014]). Hickingbottom teaches dual checkpoint targeting is a better way to suppress both checkpoint pathways and more specifically targets CTLA-4/PD-1 double positive cells that appear critical to re-establishing an anti-tumor immune response (Hickingbottom; [0013]). Hickingbottom teaches Xmab20717 is administered once between about 12 and about 17 days with a preferred embodiment being once every 15 days at a dose between 0.05 mg/kg to 12 mg/kg (Hickingbottom; [0109]; [0114]). Hickingbottom teaches a clinical trial design with a dosing schedule to include 2 doses in each 28-day cycle on Days 1 and 15 with 6 dose levels of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg where Xmab20717 was generally well tolerated where patients exhibited a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Hickingbottom; Example 1, [0146]-0151]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the PD-1 x CTLA-4 bispecific antibodies of ‘571 with the method of treating patients with ovarian cancer and stimulating immune cells (i.e. T cells) by administering the antibody once every 3 weeks of Cogswell with the specific doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to use the PD-1 x CTLA-4 bispecific antibody of ‘571 in the recited dosing regimens of Cogswell and Hickingbottom in order to effectively treat a patient with ovarian and clear cell carcinoma and enhance the proliferation of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen (once every 3 weeks) including the induction and maintenance dosing schedule of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer the PD-1 x CTLA-4 bispecific molecule of ‘571 with the induction and maintenance dosing schedule of Cogswell so that patients with cancer can achieve their maximum clinical benefit including reducing in tumor size and an increase in clinical activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule including the induction and maintenance period of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom since Cogswell teaches patients clinical benefit from the administration of anti-PD-1 and anti-CTLA-4 antibodies for an induction period and maintenance period and Hickingbottom teaches dual PD-1 x CTLA-4 targeting is a better way to suppress the checkpoint pathways and doses between 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg were well tolerated by patients where they exhibited a burst of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines. Therefore, a person of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific antibody of ‘571 with the dosing regimen schedule of Cogswell with the doses of Xmab27017 of Hickingbottom to yield predictable results of increasing the clinical efficacy of the PD-1 x CTLA-4 bispecific antibody by enhancing CD4+ and CD8+ T cell response.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated the combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell in order to effectively deliver the bispecific molecule to a patient with specific instructions for its intended use.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31 and 37-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-27 and 29-32 of copending Application No. 18/499,658, Cogswell, and Hickingbottom as applied to claims 31-36, 39-47, and 49-50 above in further view of US Patent Application Publication 2019/0161548 A1 (IDS filed on 8/30/2023; Reference US20; "Johnson").
‘658, Cogswell, and Hickingbottom have been discussed above. ‘658, Cogswell, and Hickingbottom differ from the claimed invention in regards to the PD-1 x CTLA-4 bispecific molecule’s polypeptide chain’s amino acid sequences of instant claims 37-38.
However, Johnson teaches that there is a need to improve compositions capable of more vigorously directing the body’s immune system to attack cancer cells, especially to lower therapeutic concentrations and/or with reduced side effects and targeting both PD-1 and CTLA-4 promotes the activation and continued activation of the immune system (Johnson; [0020]-[0021]). The proposed PD-1 x CTLA-4 bispecific molecule, DART D, when administered to a murine model with GVHD, markedly enhanced T cell proliferation (both T cell counts and expression of Ki-67), increased lymphocyte count, increased globulin levels, and increased spleen and thymus organ weights (Johnson; [0593]). (Reference antibody, DART D, comprises reference SEQ ID NO:100 is 100% sequence identical to instant SEQ ID NO:41 which further comprises 100% sequence identity to instant SEQ ID NO:5 (instant VHPD-1 CDRH1, 2, and 3) between amino acids 117-235 and to instant SEQ ID NO:9 (instant VLCTLA-4 CDRL1, 2, and 3) between amino acids 1-111. Reference SEQ ID NO:99 is 100% sequence identical to instant SEQ ID NO:40 which further comprises 100% sequence identity to instant SEQ ID NO:1 (instant VLPD-1 CDRL1, 2, and 3) between amino acids 1-111 and instant SEQ ID NO:13 (VHCTLA-4 CDRH1, 2, and 3) between amino acids 120-237) (Johnson; [0324]-[0333]; Table 9; Figure 3C).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to have modified the method of treating a patient with a PD-1 x CTLA-4 bispecific molecule of ‘658 with the two polypeptide chains SEQ ID NOs:40 and the two polypeptide chains SEQ ID NO:41 with of Johnson with reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification since Johnson teaches the bispeciifc molecule comprising two polypeptide chains of SEQ ID NO:41 and two polypeptide chains of SEQ ID NO:40 enhance T cell proliferation (both T cell counts and expression of Ki-67), increased lymphocyte count, increased globulin levels, and increased spleen and thymus organ weights. Therefore, one of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘658 with the two polypeptide chains of each of SEQ ID NOs:41 and 40 to yield a predictable result of enhancing T cell proliferation and a patient’s overall therapeutic response.
This is a provisional nonstatutory double patenting rejection.
Claim 31-39, 47, and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82, 94-95, and 98 of copending Application No. 18/836,888 (reference application) as evidenced by Luke et al (PTO-892; page 2, Reference W; “Luke”). Although the claims at issue are not identical, they are not patentably distinct from each other because '888 teaches in reference claim 82 a method of treating a cancer in a subject in need thereof, comprising administering an anti-B7-H3 antibody-drug conjugate (B7-H3-ADC) and a PD-1 X CTLA-4 bispecific molecule to said subject; wherein said PD-1 X CTLA-4 bispeciifc molecule is lorigerlimab of reference claim 94 (it is noted lorigerlimab, or MGD019 is the same PD-1 x CTLA-4 bispecific molecule of the instant invention (see Luke); see instant specification, [00123], and reference specification, [0185]-[0189]); wherein said PD-1 X CTLA-4 bispecific molecule is lorigerlimab, wherein said lorigerlimab is administered at a dose of: (i) about 1 mg/kg, about 3 mg/kg, or about 6 mg/kg every 3 weeks of reference claim 95; wherein said cancer is clear cell carcinoma or ovarian cancer of reference claim 98.
Therefore, ‘888 anticipates claims 31-39, 47, and 49. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31, 40-46 and 51-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82, 94-95, and 98 of copending Application No. 18/836,888 in view of WO 2013/173223 A1 (PTO-892; Reference O; "Cogswell") and WO 2020/205516 A1 (PTO-892; Reference N; “Hickingbottom”).
‘888 has been discussed above. ‘888 differs from the claimed invention in regards to the specific dosing regimen schedule of instant claims 40-46, a method of stimulating immune cells of instant claim 51-52, and a pharmaceutical kit of instant claim 53.
However, Cogswell does teach combination treatment for patients with ovarian cancer using anti-PD-1 and anti-CTLA-4 antibodies to potentiate an endogenous immune response either stimulating the activation of the endogenous response or inhibiting the suppression of the endogenous response (Cogswell; Abstract; page 10, lines 1-4, 15-18; page 39, lines 9-12; page 60, lines 9-34; Example 3). Cogswell teaches a preferred concurrent dosing regimen to include an induction dosing schedule comprising combined administration of the anti-PD-I and anti-CTLA-4 Abs at a dosing frequency of once every 3 weeks for at least 2, 4, 6, 8, or 12 doses; followed by (ii) a maintenance dosing schedule comprising combined administration of the anti-PD- I and anti-CTLA-4 antibodies at a dosing frequency of once every 2 to 12 or more weeks for up to 8 doses, or for as long as clinical benefit is observed, or until unmanageable toxicity or disease progression occurs (Cogswell; page 58, lines 24-30; page 62, lines 10-20; Example 4; Example 15). The dosing regimens are adjusted to provide optimum desired response i.e. therapeutic response or minimal adverse effects (Cogswell; page 36, lines 28-29). The treatment can be combined with effectively combined with standard cancer treatments including chemotherapy, radiation, surgery, or hormone deprivation in order to increase cancer cell death to increase the levels of tumor antigen in the antigen presentation pathway (Cogswell; page 63, lines 25-34). Cogswell additionally teaches a clinical trial design studying the efficacy of combination anti-PD-1 and anti-CTLA-4 in MEL patients where 21 of 52 patients achieved objective responses, 16 patients had ≥ 80% tumor reduction at 12 weeks including 5 complete responses and overall evidence of clinical activity was observed in 65% of patients (Cogswell; page 127-128; Table 10; Figures 14A and 15-17; Example 17). Cogswell additionally teaches a pharmaceutical kit comprising the anti-PD-1 and anti-CTLA-4 antibodies including instructions for the intended use of the contents (Cogswell; page 72, lines 31-33; page 72, lines 1-9).
Hickingbottom teaches methods of improving delivery of a PD-1 x CTLA-4 bispecific antibody, Xmab20717, to human subjects who possess cancer (Hickingbottom; Abstract; [0014]). Hickingbottom teaches dual checkpoint targeting is a better way to suppress both checkpoint pathways and more specifically targets CTLA-4/PD-1 double positive cells that appear critical to re-establishing an anti-tumor immune response (Hickingbottom; [0013]). Hickingbottom teaches Xmab20717 is administered once between about 12 and about 17 days with a preferred embodiment being once every 15 days at a dose between 0.05 mg/kg to 12 mg/kg (Hickingbottom; [0109]; [0114]). Hickingbottom teaches a clinical trial design with a dosing schedule to include 2 doses in each 28-day cycle on Days 1 and 15 with 6 dose levels of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg where Xmab20717 was generally well tolerated where patients exhibited a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Hickingbottom; Example 1, [0146]-0151]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the PD-1 x CTLA-4 bispecific antibodies of ‘571 with the method of treating patients with ovarian cancer and stimulating immune cells (i.e. T cells) by administering the antibody once every 3 weeks of Cogswell with the specific doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to use the PD-1 x CTLA-4 bispecific antibody of ‘571 in the recited dosing regimens of Cogswell and Hickingbottom in order to effectively treat a patient with ovarian and clear cell carcinoma and enhance the proliferation of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen (once every 3 weeks) including the induction and maintenance dosing schedule of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer the PD-1 x CTLA-4 bispecific molecule of ‘571 with the induction and maintenance dosing schedule of Cogswell so that patients with cancer can achieve their maximum clinical benefit including reducing in tumor size and an increase in clinical activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule including the induction and maintenance period of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen schedule of Cogswell with the specific doses (0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg) of Xmab20717 administered one days 1 and 15 of a 28-day cycle of Hickingbottom since Cogswell teaches patients clinical benefit from the administration of anti-PD-1 and anti-CTLA-4 antibodies for an induction period and maintenance period and Hickingbottom teaches dual PD-1 x CTLA-4 targeting is a better way to suppress the checkpoint pathways and doses between 0.15, 0.3, 1.0, 3.0, 6.0, and 10.0 mg/kg were well tolerated by patients where they exhibited a burst of CD4+ and CD8+ T cells and induction of IFN-inducible chemokines. Therefore, a person of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific antibody of ‘571 with the dosing regimen schedule of Cogswell with the doses of Xmab27017 of Hickingbottom to yield predictable results of increasing the clinical efficacy of the PD-1 x CTLA-4 bispecific antibody by enhancing CD4+ and CD8+ T cell response.
It would also have been obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen of Cogswell and Hickingbottom with stimulating the immune system of Hickingbottom with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen of Cogswell and Hickingbottom with stimulating the immune system of Hickingbottom since both Cogswell and Hickingbottom teach targeting both PD-1 and CTLA-4 checkpoint pathways establishes an anti-tumor immune response by stimulating both CD4+ and CD8+ T cells. Therefore, one of ordinary skill in the art would combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the dosing regimen of Cogswell and Hickingbottom with stimulating the immune system of Hickingbottom to yield a predictable result of enhancing CD4+ and CD8+ T cell responses and anti-tumor activity.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell with reasonable expectation of success. One of ordinary skill in the art would have been motivated the combine the PD-1 x CTLA-4 bispecific molecule of ‘571 with the pharmaceutical kit of Cogswell in order to effectively deliver the bispecific molecule to a patient with specific instructions for its intended use.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/LEAH ELIZABETH STEIN/ Examiner, Art Unit 1641
/NORA M ROONEY/ Primary Examiner, Art Unit 1641
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