DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 35-36, 38-43, 45-50, and 52-55; drawn to methods of treating cancer in a subject comprising the use of an antigen-binding molecule that binds to VISTA and comprises the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:305; HC-CDR2 having the amino acid sequence of SEQ ID NO:306; HC-CDR3 having the amino acid sequence of SEQ ID NO:307; LC-CDR1 having the amino acid sequence of SEQ ID NO:41; LCCDR2 having the amino acid sequence of SEQ ID NO:308; and LC-CDR3 having the amino acid sequence of SEQ ID NO:43; species of cancer: solid tumor) in the reply filed on 7/24/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 37, 44, and 51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-34 have been canceled.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 7/24/2026, 9/30/2024, and 2/1/2024 are in compliance with the provisions of 37 CFR 1.97 and have been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), lack of written description
4. 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.
4a. Claims 35-36, 38-43, 45-50, and 52-55, 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Independent claim 35, for example, is drawn to “a method of treating a cancer in a subject, comprising administering to a subject a therapeutically-effective amount of: (i) an antigen-binding molecule that binds to VISTA, and (ii) an agent that inhibits PD-1-mediated signaling; wherein the antigen-binding molecule that binds to VISTA inhibits VISTA-mediated signaling independently of Fc-mediated function, and wherein the antigen-binding molecule that binds to VISTA displays cross-reactivity with both human VISTA and mouse VISTA”.
Independent claim 42 recites “a method of treating a cancer in a subject, comprising administering to a subject a therapeutically-effective amount of an antigen-binding molecule that binds to VISTA, wherein the antigen-binding molecule that binds to VISTA inhibits VISTA-mediated signaling independently of Fc-mediated function, and wherein the antigen-binding molecule that binds to VISTA displays cross-reactivity with both human VISTA and mouse VISTA; wherein the method further comprises administering to the subject a therapeutically effective amount of an agent that inhibits PD-1- mediated signaling.”
Independent claim 49 recites “a method of treating a cancer in a subject, comprising administering to a subject a therapeutically-effective amount of an agent that inhibits PD-1-mediated signaling; wherein the method further comprises administering to the subject a therapeutically effective amount of an antigen-binding molecule that binds to VISTA, wherein the antigen-binding molecule that binds to VISTA inhibits VISTA-mediated signaling independently of Fc-mediated function, and wherein the antigen-binding molecule that binds to VISTA displays cross-reactivity with both human VISTA and mouse VISTA.”
The claims require administration of “a VISTA antibody”. The claims, however, do not require that the “VISTA antibody” recited in claims, 35, 42, and 49, possess any particular conserved structure, or other distinguishing feature.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, and any combination thereof. In this case, the only factor present in the claim that is sufficiently disclosed is a recitation of a desired activity, “an antigen-binding molecule that binds to VISTA” and “an agent that inhibits PD-1-mediated signaling.” The specification does not identify any particular portion of the structure of the antibodies, nor does it provide a disclosure of structure/function correlation. The distinguishing characteristics of the claimed genus for the VISTA and PD-1 or PD-L1 antibodies are not described. Accordingly, the specification does not provide adequate written description of the claimed genus of antibodies to be administered in the claimed method.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 [10 USPQ2d 1614] (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”). Thus, an applicant complies with the written-description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572.
See University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 (DC WNY 2003) and University of Rochester v. G.D. Searle & Co. et al. CAFC [(03-1304) 13 February 2004]. In University of Rochester v. G.D. Searle & Co. a patent directed to method for inhibiting prostaglandin synthesis in human host using an unspecified compound, in order to relieve pain without side effect of stomach irritation, did not satisfy written description requirement of 35 U.S.C. §112, since the patent described the compound's desired function of reducing activity of the enzyme PGHS-2 without adversely affecting PGHS-1 enzyme activity, but did not identify said compound, since invention consists of performing “assays” to screen compounds in order to discover those with desired effect. The patent did not name even one compound that assays would identify as suitable for practice of invention, or provide information such that one skilled in art could identify suitable compound. And since specification did not indicate that compounds are available in public depository, the claimed treatment method cannot be practiced without compound. Thus, the inventors cannot be said to have “possessed” claimed invention without knowing of a compound or method certain to produce compound. Thus, said patent constituted an invitation to experiment to first identify, then characterize, and then use a therapeutic a class of compound defined only by their desired properties.
Therefore, the full breadth of the claims fails to meet the written description provision of 35 U.S.C. §112, first paragraph. In the instant case, for example, Applicants have failed to describe which “VISTA antibodies” and “PD-1 or PD-L1 antibodies” have the desirable property of treating cancer in a subject in need thereof. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision.
To demonstrate possession of a method of treatment one must provide substantially more than the description of a compound or collection of related compounds having an in vitro activity, in combination with a hypothesis that the administration of a compound having that activity to an individual suffering from a particular disease or disorder might produce a beneficial effect. What is required is an established nexus between the administration of such a compound to an individual and a beneficial result consequent thereto. Such a nexus can be established by the presentation of evidence demonstrating clinical efficacy of the claimed method in the treatment of a particular disease or disorder, demonstrating efficacy of that method in the treatment of an art accepted animal model of a disease or disorder wherein that model is known to be reasonably predictive of the efficacy of a treatment protocol in the treatment of that disease or disorder, or providing evidence of an in vitro activity for the recited compound in combination with a showing that other compounds possessing that activity (mode of action) have been shown to have clinical efficacy in the treatment of the recited disease or disorder. The instant specification fails to show possession of the claimed method as of the effective filing date of the instant application because it provides none of these.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. § 112(a), "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers. 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002).
As discussed above, Applicant has claimed a VISTA antibody encompassing variants of the amino acid sequence of the CDRs having one or several amino acid substitutions, deletions, or additions. Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
In the instant case, the specification discloses on page 47, lines 32-36, discloses:
“In some embodiments the antigen-binding molecule comprises a VH region according to any one of (1) to (76) above, and a VL region according to any one of (77) to (173) above.
In embodiments in accordance with the present invention in which one or more amino acids are substituted with another amino acid, the substitutions may be conservative substitutions, for example according to the following Table. In some embodiments, amino acids in the same block in the middle column are substituted.”
Additionally, the specification discloses on page 48, lines 1-4, discloses:
“In some embodiments, substitution(s) may be functionally conservative. That is, in some embodiments the substitution may not affect (or may not substantially affect) one or more functional properties (e.g. target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule.”
Therefore, Applicant’s claims encompass “variants” comprising one or more amino acid substitutions in the heavy and light chain CDRs.
Applicant is reminded that the courts have long ruled that “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.” See University of Rochester. 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, CDR2 and CDR3, 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 the heavy chain CDRs and the light chain CDRs are critical in maintaining the antigen binding specificity and affinity. It is also known that single amino acid changes in the CDRs can abrogate the antigen binding function of an antibody (Rudikoff et al., 1982, see entire document, particularly the abstract and the middle of the left column of page 1982). However, as discussed above, only the 6 CDRs for the antibody having a heavy chain VH-CDR1, VH-CDR2, and VH-CDR3 as set forth in SEQ ID NOs: 304, 306 and 307, and light chain VL-CDR1, VL-CDR2, and VL-CDR3 as set forth in SEQ ID NOs: 41, 308 and 43, have been described.
Indeed, in AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) the court ruled that all of the antibodies disclosed by AbbVie were all structurally similar as they were variants of a starting antibody named Joe9 and therefore did not serve to inform artisans as to the breadth of structures which had the recited function of cytokine binding. In the instant application, the instant claims recite antibodies to be used in the claimed methods while the specification does not disclose structures which necessarily have the requisite
functions. The instant specification fails to disclose sufficient structural information to indicate to artisans that Applicant had possession of the various VISTA antibodies as presently claimed. Therefore, it appears that the broad genus of antibodies recited in Applicant’s claims lacks adequate written description because there does not appear to be sufficient correlation between the structure of the antibodies in question and their recited functional activities. As such a skilled artisan would reasonably conclude that Applicant was not in possession of the recited genus of antibodies. Therefore, there is insufficient written description for the genus of antigen-binding immunoglobulin molecules having the claimed “limitations” at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 USC 112.
Appellant has been reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115.)
Claim Rejections - 35 USC § 112(a), lack of enablement
4b. Claims 35-36, 38-43, 45-50, and 52-55 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.
Independent claim 35, for example, is drawn very broadly to a method of treatment of all cancers in a subject by administering “a method of treating a cancer in a subject, comprising administering to a subject a therapeutically-effective amount of: (i) an antigen-binding molecule that binds to VISTA, and (ii) an agent that inhibits PD-1-mediated signaling; wherein the antigen-binding molecule that binds to VISTA inhibits VISTA-mediated signaling independently of Fc-mediated function, and wherein the antigen-binding molecule that binds to VISTA displays cross-reactivity with both human VISTA and mouse VISTA.”
However, the specification fails to provide any guidance for such a method by administering all VISTA antibodies.
The specification on page 13, lines 15-30, discloses:
“Also provided is a method of treating or preventing a cancer or an infectious disease, comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule, CAR, nucleic acid or a plurality of nucleic acids, expression vector or a plurality of expression vectors, cell, or composition of the invention.
In some embodiments the cancer is selected from: a cancer comprising cells expressing VISTA, a cancer comprising infiltration of cells expressing VISTA, a cancer comprising cancer cells expressing VISTA, a hematological cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, T cell lymphoma, multiple myeloma, mesothelioma, a solid tumor, lung cancer, non-small cell lung carcinoma, gastric cancer, gastric carcinoma, colorectal cancer, colorectal carcinoma, colorectal adenocarcinoma, uterine cancer, uterine corpus endometrial carcinoma, breast cancer, triple negative breast invasive carcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, thyroid cancer, thymoma, skin cancer, melanoma, cutaneous melanoma, kidney cancer, renal cell carcinoma, renal papillary cell carcinoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer, ovarian carcinoma, ovarian serous cystadenocarcinoma, prostate cancer and/or prostate adenocarcinoma.”
However, other than this disclosure in the instant specification, there is no guidance for a method of treating every and all cancers by administering a VISTA antibody. There is absolutely no disclosure in the instant specification with respect to the administration of the claimed VISTA antibodies for the treatment of every and all cancers. The specification clearly fails to supply the guidance that would be needed by a routine practitioner to treat cancer.
The instant specification is attempting to link cancer treatment by administering a VISTA antibody. However, Applicants have failed to demonstrate, using a conventional cancer model for mice, that administering a VISTA antibody can treat every and all cancers. On pages 157-159 of the specification, Applicant has only disclosed treatment of solid tumors.
The instant specification has failed to demonstrate the nexus between treatment of all cancers ranging from leukemia to lymphoma and administration of VISTA antibodies. The instant specification has also failed to disclose the duration and quantity of administration of the VISTA antibodies to a subject depending on the severity of the cancer for treatment, which are important parameters. In the absence of this guidance, a practitioner would have to resort to a substantial amount of undue experimentation involving the variation in the amount and duration of administration of the VISTA antibodies in the method of the instant invention.
In Genentech v. Novo Nordisk, 108 F.3d 1361, 42 U.S.P.Q.2d 1001, the CAFC stated that “Genentech's arguments, focused almost exclusively on the level of skill in the art, ignoring the essence of the enablement requirement. Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 86 S.Ct. 1033, 1042-43, 16 L.Ed.2d 69, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
Therefore, this requirement has not been met in the instant specification with respect to providing guidance for the treatment of every and all cancers cancer by administering VISTA antibodies.
The instant situation is directly analogous to that which was addressed in In re Colianni, 195 U.S.P.Q. 150, C.A.F.C., which held that a "disclosure that calls for application of 'sufficient'ultrasonic energy to practice claimed method of fusing bones but does not disclose what'sufficient' dosage of ultrasonic energy might be or how those skilled in the art might select appropriate intensity, frequency, and duration, and contains no specific examples or embodimentby way of illustration of how claimed method is to be practiced does not meet requirements of 35 U.S.C. § 112 first paragraph".
In view of this unpredictability in the treatment of every and all cancers by administering the claimed VISTA antibodies, there cannot be said to be any reasonable expectation of success at the in vivo application of the claimed method. Therefore, it would require undue experimentation for the ordinary artisan to determine how to use the claimed method.
The CAFC decision (Genentech Inc. v. Novo Nordisk, 42 USPQ2d 1001, 1997) expressly states that:
"When there is no disclosure of any specific starting material or of any of the conditions underwhich a process can be carried out, undue experimentation is required; there is a failure to meetthe enablement requirement that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art. It is the specification, not the knowledge of one skilled inthe art, which must supply the novel aspects of an invention in order to constitute adequateenablement".
The factors listed below have been considered in the analysis of enablement [see MPEP §2164.01(a) and In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)]:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Given the breadth of claims 35-36, 38-43, 45-50, and 52-55, in light of the predictability of the art as determined by the number of working examples, the level of skill of the artisan, and the guidance provided in the instant specification and the prior art of record, it would require undue experimentation for one of skill in the art to practice the claimed invention.
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. Given the inherent unpredictability of physiological activity, which would include biological processes, i.e., methods of treatment, a certain amount of enablement beyond mere assertion must be required.
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states "[W]here there is "no indication that one skilled in [the] art would accept without question statements [as to the effects of the claimed drug products] and no evidence has been presented to demonstrate that the claimed products do have those effects," an applicant has failed to demonstrate sufficient utility and therefore cannot establish enablement" and "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Therefore, when an application is drawn to a method of treatment it is reasonable that actual evidence be submitted for one of skill in the art to accept that the method would produce the desirable effects.
In the context of determining whether sufficient "utility as a drug, medicant, and the like in human therapy" has been alleged, "it is proper for the examiner to ask for substantiating evidence unless one with ordinary skill in the art would accept the allegations as obviously correct." In re Jolles, 628 F.2d 1322, 1332 ([CCPA] 1980), citing In re Novak, 306 F.2d 924 ([CCPA] 1962); see Application of Irons, 340 F.2d 974, 977- 78 ([CCPA] 1965) .... However, where there is "no indication that one skilled in [the] art would accept without question statements [as to the effects of the claimed drug products] and no evidence has been presented to demonstrate that the claimed products do have those effects," an applicant has failed to demonstrate sufficient utility and therefore cannot establish enablement. Novak, 306 F.2d at 928.
Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 132375 USPQ2d 1297 (Fed. Cir. 2005) (bracketed material in original).
With these teachings in mind, an enabling disclosure in the form of a nexus between treatment of every and all cancers by administering the claimed VISTA antibodies is required.
Furthermore, the term “cancer” encompasses treatment of all cancers including melanoma, leukemias, etc. recited in the specification on page 13, lines 20-30, and the Examiner presumes the conditions contemplated encompass all these conditions. The instant specification does not adequately teach how to effectively treat all these other conditions to reach a therapeutic endpoint by administering the claimed VISTA antibodies. Art recognized methods for treatment of malignancies are set forth in the Merck Manual (pages 986-995). The Merck Manual indicates that absent any data, it would require undue experimentation to practice the claimed method of treatment of all malignancies.
In the instant case, a method of treating leukemia, is very different from a method of treating melanoma or a brain cancer. The treatment of malignancies has been the subject of intense study for the past several decades. Many promising treatments and therapies have been identified via in vitro experiments, and have not lived up to expectations when tested in vivo. In fact, the number of such treatments, which have failed to live up to their promise exceeds those, which have been performed as hoped by orders of magnitude. The claims encompass malignancies of bone, brain, etc. The disclosure fails to teach one of ordinary skill in the art a method of treatment of all types of malignancies whether adenomas, glioblastomas, neuroblastomas etc. The effectivity of the claimed method against one type of tumor malignancy may be different from another specific type of malignancy depending on the type of cells involved and the developmental stage of the malignancy. With respect to the disparate tissues, the skilled artisan would have to undergo undue experimentation to determine if there is a therapeutically effective amount of the claimed products to be utilized for treating the various types of malignancies because with respect to dosage, experiments in vitro where a single cell type is present cannot be correlated to in vivo conditions where several different cell types are present. It would not be reasonable to expect the claimed products to work on the various types of aforementioned malignancies because it is well known that results obtained on a tissue such as skin are generally not reasonably predictive of results to be expected for neural and other tissues. It would be difficult to achieve treatment of malignancies in nerve or bone tissue as opposed to treatment of leukemia, which is certainly not representative of the various types of malignancies. Thus, it would require undue experimentation on the part of the skilled artisan to use the claimed method for treated as recited, in the absence of sufficient information to predict the results with an adequate degree of certainty. In view of this unpredictability in the treatment of different malignancies, there cannot be said to be any reasonable expectation of success at the in vivo application of a potential therapy, especially in view of the fact that the current specification as filed presents no working examples pertaining to the method of treatment of various malignancies in vivo. Therefore, a method for treating all cancers by administration of VISTA antibodies as recited in the claims has not been enabled by the specification.
Claim Rejections - 35 U.S.C. § 112(b)
5. 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.
5a. Claims 35-36, 38-43, 45-50, and 52-55 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 pre-AIA the applicant regards as the invention.
Claim 35 is rejected as vague and indefinite for several reasons.
Claim 35, line 2, is vague and indefinite because it recites “VISTA”. The full meaning of an acronym should be recited at its first recitation in an independent claim. The claim must be amended to recite “V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA)” to obviate this rejection (See Specification page 1, line 25).
Claim 35, lines 2, 3, 5, is vague and indefinite because it recites “antigen-binding molecule that binds to VISTA”. The metes and bounds of the term “antigen-binding molecule” are unclear because the term as defined in the specification also encompasses other “antigen-binding molecules”, for example, nanobodies, while the only “antigen-binding molecule” described in the specification is an antibody to VISTA (See Specification page 1, line 7; page 24, lines 2-36). Appropriate correction of the claim is required to obviate this rejection.
Similarly, claims 36, 38, 42-43, 45, 49-50, and 52 are rejected as vague and indefinite for the recitation of “antigen-binding molecule”.
Claims 41, 44, and 55 are rejected on the basis that the claims contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The claims recite genus and species within the same claim, for example general cancers such as “cancer comprising cells expressing VISTA, a cancer comprising infiltration of cells expressing VISTA, a cancer comprising cancer cells expressing VISTA, …a solid tumor….” and specific cancers such as “lung cancer, non-small cell lung carcinoma, gastric cancer”. Appropriate correction of the claims is required to obviate this rejection.
Claims 39-40, 46-47, and 53-54 are rejected as vague and indefinite insofar as they depend on the above rejected claims for their limitations.
Claim Rejections - 35 USC § 102
6. 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.
6a. Claims 35, 39-42, 46-49, and 53-55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Louise Lines et al (2014) as evidenced by Zhang et al (2024).
The reference teaches a method of treating melanoma by administering a VISTA antibody with a PD-1 antibody, nivolumab (See page 511, Figure 1; page 512, column 1, last paragraphs; page 514, Figure 2). The VISTA antibody recited in the reference would inherently inhibit VISTA-mediated signaling of Fc-mediated function. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)
Therefore, the reference anticipates claims 35, 39-42, 46-49, and 53-55.
Zhang et al has been cited in the instant rejection for the disclosure that VISTA is more highly conserved between mice and humans than all other members of the family, with 76% sequence identity and up to 91% identity of the cytoplasmic domain (See page 2348, column 1, last 2 lines, and column 2, lines 1-4). The Examiner has presented evidence to show inherency, and the burden is on Applicant to show the difference.
Claim rejections-Double Patenting
Non-statutory double patenting rejection (obviousness-type)
The non-statutory 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 non-statutory double patenting rejection is appropriate where the claims at issue 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); and 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 non-statutory 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 non-statutory 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.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
7a. Claims 35-36, 38-43, 45-50, and 52-55 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 10-13 of US Patent No. 11,873,346 (‘346) in view of Louise Lines et al (2014).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 10 in ‘346 (having the same 7 inventors as the instant application) recites a method for of treating a cancer in a subject, comprising administering to a subject a therapeutically effective amount of an antigen-binding molecule comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the antigen-binding molecule binds specifically to and displays cross-reactivity with both human VISTA and mouse VISTA, wherein the antigen-binding molecule inhibits VISTA-mediated signalling independently of Fc-mediated function, and wherein the antigen-binding molecule comprises: a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:305
HC-CDR2 having the amino acid sequence of SEQ ID NO:306
HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and
a VL region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:41
LC-CDR2 having the amino acid sequence of SEQ ID NO:308
LC-CDR3 having the amino acid sequence of SEQ ID NO:43. The reference is silent with respect to administering an agent that inhibits PD-1-mediated signaling, together with the VISTA antibody.
Instant independent claim 35 recites a method of treating a cancer in a subject, comprising administering to a subject a therapeutically-effective amount of: (i) an antigen-binding molecule that binds to VISTA, and (ii) an agent that inhibits PD-1-mediated signaling; wherein the antigen-binding molecule that binds to VISTA inhibits VISTA-mediated signaling independently of Fc-mediated function, and wherein the antigen-binding molecule that binds to VISTA displays cross-reactivity with both human VISTA and mouse VISTA.
Louise Lines et al teaches that anti-PD1 antibodies together with anti-VISTA antibodies have been showing great progress in immunotherapy of cancers, with synergy when targeted in combination (See page 511, Figure 1; page 514, Figure 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of ‘346 by administering VISTA antibodies together with PD-1 antibodies as taught by Louise Lines et al because Louise Lines et al disclose the regression of cancer and long-term survival rate of cancer patients administered both, PD-1 antibodies and VISTA antibodies. The person of ordinary skill in the art would have been motivated to modify the method of ‘346 and expect success because Louise Lines teaches that since VISTA and PD1 checkpoint pathways are independent, failure of one blockade strategy does not mean that a patient would fail in the other strategy, and multiple blockade agents could combine synergistically (See page 514, Figure 2). To combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for very same purpose would have been obvious to one of ordinary skill in the art at the time the invention was made. The combination would have been obvious to the skilled artisan and the results achieved would have been expected (In re Kerkhoven, 205 USPQ 1069).
The patented claims if infringed upon would also result in infringement of the claims of the instant application. Allowance of the pending claims, therefore, would have the effect of extending the enforceable life of the allowed claims beyond the statutory limit.
Conclusion
No claim is allowed.
Claims 35-36, 38-43, 45-50, and 52-55 are rejected.
Advisory Information
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1674
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