DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-3, 11-13, and 16 are examined herein.
Claims 4-10, and 14-15 are withdrawn (see restriction/election below).
Priority
This application is filed 09/12/2023 and claims the benefit of domestic priority as below:
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Information Disclosure Statements
Two IDS(s) received on 9/12/2023, and 2/12/2024 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant elects Group I, claims 1-3, 11-13, and 16, are drawn to a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof including use for an adjuvant in vaccines, without traverse in the reply field on 05/18/2026 is acknowledged. Claims 4-6 (Group II), and claims 7-10, and 14-15 (Group III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method of use (Group II) and method of producing (Group III), there being no allowable generic or linking claim.
Applicant elects the one compound as CF508 in claim 2 as the species, without traverse in the reply field on 05/18/2026 is acknowledged.
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The claims 1-3, 11-13, and 16 read on the elected species.
If the elected specie is not identified in the prior arts, the elected specie would be allowable if
an independent claim were drafted with that specie alone. (see MPEP 802.03)
The elected specie was not identified in the prior art. Further, the Examiner expanded the
search to alternative species within the genus of Formula (I), and/or claim 2, and subsequent examination is based on alternative species expansion. Accordingly, claims 1-3, 11-13, and 16 read on the elected species and alternative species, and will be examined on their merits. No further claims are withdrawn.
With respect to the expanded species, the art is rejected under 35 USC 112, 35 USC 102, and 35 USC 103 below.
Claim Interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111).
With respect to claims 11-13, claims 11-13 are interpreted as product claims directed to the compound of claim 1. The recitation relating to use as an adjuvant, including a vaccine adjuvant, and the recitations relating to a vaccine, an antigen, or treatment or prevention of disease are interpreted as statements of intended use or intended use environment. Under MPEP 2111.02, statements reciting the purpose or intended use of a claimed invention are evaluated to determine whether the recited purpose or intended use results in a structural difference between the claimed invention and the prior art. Here, the intended use language does not further limit the structure or composition of the claimed compound. Therefore, claim 11-13 are not further limited by the recited intended use language.
With respect to claim 16, claim 16 is interpreted as a kit claim requiring at least the compound of claim 1, an antigen and instructions for treating or preventing an infectious disease or cancer. The specification defines that the container may include at least one vial, tube, flask, bottle, syringe, or other container device. Therefore, providing a pharmaceutical compound in a container would have been a conventional and predictable way to store, preserve, transport, and dispense the compound for its intended pharmaceutical use. In addition, the instructions are considered part of the claimed kit, but any therapeutic or prophylactic result stated in the instructions is evaluated only according to the extent it structurally or functionally limits the kit and its use.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
The lines, numbers and lettering are not clean, well-defined, sufficiently dense and dark, overlap, and/or well defined in Figure(s) 28-30, 47-51, 53, and 87. See 37 CFR 1.84(l) and (q). The graphs, in particular, have significant overlap, making them difficult to interpret.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 11-13, and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for selected embodiments involving CF501 in combination with SARS-CoV-2 RBD-Fc and certain additional selected viral antigen contexts, does not reasonably provide enablement for the full scope of the claimed use of the compound as an adjuvant for vaccines comprising broadly recited antigens, or the claimed kit comprising the compound, an antigen, and instructions for treating or preventing an infectious disease or a cancer, without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant claims 11-13 are drawn to the compound of claim 1 or a pharmaceutically acceptable salt thereof, for use as an adjuvant, including as an adjuvant for a vaccine. The vaccine may include multiple vaccine types, including inactivated vaccines, live-attenuated vaccines, subunit vaccines, and nucleic acid vaccines, including mRNA and DNA vaccines. Claim 12 further recites that the vaccine comprises an antigen selected from a cancer antigen, viral antigen, bacterial antigen, parasitic antigen, and fungal antigen. Claim 13 further recites viral antigens selected from HIV antigen, an influenza antigen, and a coronavirus antigen, including antigens from HCOV- 229E, HCOV-OC43, SARS-COV, HCOV-NL63, HCOV-HKU1, MERS-COV, Varicella-zoster virus (VZV) and SARS-COV-2 such as SARS-CoV-2 Omicron mutant, preferably SARS-CoV-2 RBD-Fc protein or gE protein of Varicella zoster virus. Claim 16 is drawn to a kit comprising the compound of claim 1, an antigen, and instructions for treating or preventing an infectious disease or a cancer. Thus, the claims broadly encompass use of the claimed compound as an adjuvant across multiple vaccine platforms, antigen classes, infectious disease contexts, and cancer vaccine contexts, while claim 16 further encompasses kits for treating or preventing infectious disease or cancer.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, and state and predictability of the art
The instant claims relates to use of stimulator of interferon genes (STING) agonist compounds as adjuvants in vaccine contexts and to kits comprising such compounds with antigens and instructions for treating or preventing infectious disease or cancer. Under MPEP 2164 and 2164.08, the enablement inquiry is directed to whether the specification enables the full scope of the claimed invention without undue experimentation, and the scope of enablement must be commensurate with the scope of the claims.
Adjuvant activity is not a property that can be reliably extrapolated across all antigens, vaccine platforms, infectious diseases, cancers, routes of administration, formulations, dosing regimens, and patient populations. Coffiman et al. (Vaccine adjuvants: putting innate immunity to work, Immunity., 33(4), 492-503, pub’d 10/29/2010) explains that adjuvants enhance immunity by a variety of mechanisms, and that innate immune responses strongly influence adaptive immune responses (abstract, and conclusion section). In addition, Pasquale et al. (Vaccine Adjuvants: from 1920 to 2015 and Beyond, Vaccines (Basel), 3(2), 320–343, pub’d 04/16/2015) teach that modern adjuvants are selected and designed to improve vaccine immunogenicity and that antigen/adjuvant combinations are used to shape downstream adaptive immune responses (abstract and The Immunology of Infection and Immunization section). Coffiman and Pasquale support that adjuvant effect is mechanism dependent and context dependent, rather than a property that can be assumed across all vaccine setting.
Route of administration and biodistribution further affect adjuvant performance. Schmidt et al. (The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8(+) T-cell responses: The immunological consequences of the biodistribution profile, J. Control Release, 239, 107-117, pub’d 10/10/2016) explains that administration route and biodistribution can be decisive for whether a vaccine adjuvant induces antigen specific CD8(+) T-cell responses (abstract and section 2.6/3.2), and Sarker et al. (Selection of adjuvants for vaccines targeting specific pathogens, Expert Rev. Vaccines, 18(5), 505–521, pub’d 04/22/2019) explains that proper adjuvant selection is important in vaccine formulation and that adjuvants may be selected to elicit immune responses tailored to specific pathogens (abstract and Mode of action of adjuvants section). Thus, Schmidt and Sarker support that adjuvant performance cannot be assumed without considering route of administration, biodistribution, and the desired immune endpoint, and the adjuvant/antigen/pathogen relationship is not generic or universally predictable, but instead depends on the pathogen, antigen, vaccine type, and desired immune response.
Cancer vaccine and cancer immunotherapy are likewise context dependent. Melief et al. (Therapeutic cancer vaccines, J. Clin. Invest., 125(9), 3401-3412, pub’d 07/27/2015) teaches that therapeutic cancer vaccine efficacy depends on vaccine design, antigen delivery to dendritic cells, appropriate CD4+ and CD8+ T-cell responses, and the immunosuppressive tumor microenvironment (Guidelines for the development of successful therapeutic cancer vaccines section, and Fig 3), and it shows that cancer vaccine and immunotherapy are context dependent.
For the claim 16, the claim encompasses that a kit comprising the compound of claim 1, an antigen, and instructions for treating or preventing an infectious disease or a cancer. The claim is not limited to any particular antigen, vaccine platform, infectious disease, cancer type, formulation, route of administration, dose, regimen or patient population. In view of Coffiman , Pasquale, Schmidt, Sarkar, and Melief, the ability to make and use an adjuvant containing vaccine kit depends on the identity of the antigen, the disease being targeted, the formulation, the route and mode of administration, the desired immune response, cancer, tumor and immune microenvironment.
The instant specification describes that CF501 adjuvanted RBD-Fc activated cellular and humoral immune responses in selected animal models, produced protection against SARS-CoV-2 and selected SARS related viruses, SARS-CoV-2 RBD specific antibody titers, neutralization, ELISPOT readouts, and challenge related viral load results in selected models. The specification also provides more limited data for selected additional viral antigen contexts, including selected HIV, influenza, and Varicella-zoster virus antigens.
However, those limited examples do not establish predictability across the full scope of claims 11-13, and 16. At most, the specification provides the guidance for selected viral antigen embodiments, particularly CF501 with SARS-CoV-2 RBD-Fc and closely related SARS related virus contexts. That disclosure does not reasonably enable the full claimed scope covering cancer, viral, bacterial, parasitic, and fungal antigens, all vaccine types, and kits for treating or preventing infectious disease or cancer. The specification further indicates that other STING agonist having structures similar to CF501, including CF512, CF510, CF508, and CF502, do not induce more potent binding antibodies or neutralizing antibodies relative to Alum in rabbits, and that minor structural changes may significantly influence adjuvant effects (lines 3-10, page 75). This disclosure supports the conclusion that adjuvant activity in this field is not predictably extrapolated even among structurally related STING agonists.
Accordingly, the specification and the cited references indicate that vaccine adjuvant activity, particularly, for STING agonist compound functions as an effective adjuvant depends on the particular compound, antigen, vaccine platform, immune response endpoint, dose, formulation, route of administration, biodistribution profile, and disease context. The specification does not establish that activity observed for selected embodiments can be predictably applied across the full scope of claims without undue experimentation.
The breadth of the claims
The claims are very broad insofar as they recite the compound of claim 1 for use as an adjuvant and broadly includes vaccine adjuvant use, and a kit comprising the compound of claim 1, an antigen, and instructions for treating or preventing an infectious disease or a cancer.
The claims are not limited to a particular antigen, particular cancer antigen, particular bacterial antigen, particular parasitic antigen, particular fungal antigen, particular infectious disease, particular cancer, particular vaccine platform, particular formulation, particular dose, particular route of administration, particular treatment schedule, particular patient population, or particular immunological endpoint. As taught by Coffiman , Pasquale, Schmidt, and Sarkar, adjuvant efficacy is not a generic or universally predictable property, but depends on the antigen, pathogen or disease context, vaccine platform, route of administration, biodistribution, formulation, and desired immune endpoint. As further taught by Melief, cancer vaccine performance depends on antigen selection, vaccine design, dendritic cell activation, T-cell priming, effector cell function, and the tumor immune microenvironment.
Therefore, the breadth of claims 11-13, and 16 is significant because the claims are not limited to the particular antigen/adjuvant combinations, administration conditions, or immune endpoints actually demonstrated in the specification. Rather, the claims extend across diverse antigen classes and disease contexts for which the specification provides little or no working data. The specification also does not provide a predictive structure activity relationship, formulation relationship, or antigen adjuvant relationship that would allow one of ordinary skill in the art to determine, without substantial additional experimentation, which antigens, vaccine platforms, formulations, doses, routes of administration, disease contexts, and immune response endpoints would be expected to produce the claimed adjuvant use using the compound of claim 1.
Accordingly, in view of the broad antigen classes recited in claim 12, the selected but varied viral antigens recited in claim 13, the broad kit language of claim 16, and the context dependent principles taught by cited references, the claims encompass substantially more than the selected embodiments actually demonstrated in the specification. Therefore, the breadth of claims 11-13, and 16 exceeds what is reasonably enabled by the disclosed data without undue experimentation.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides synthetic disclosure for compounds, and guidance for selected embodiments, particularly CF501 with SARS-CoV-2 RBD-Fc and certain additional viral antigen contexts. Those data may support a narrow claim directed to specific compounds, specific viral antigens, and specific vaccine/adjuvant settings. However, the specification does not provide sufficient direction for using the compound of claim 1 as an adjuvant across the full range of claimed vaccine types and antigen classes, disease contexts, and kit embodiments.
For claims 11-13, the specification does not provide reasonably specific guidance showing that the claimed compound can be used as an adjuvant with the full range of cancer antigens, viral antigens, bacterial antigens, parasitic antigens and fungal antigens. Nor does it provide adequate guidance for selecting appropriate antigens, formulations, doses, routes of administration, immunization schedules, immune response endpoints, or criteria for successful adjuvant activity across the full claim scope.
Although, the specification includes working examples involving CF501 with SARS-CoV-2 RBD-Fc and limited examples involving selected additional viral antigens, the examples are not representative of the full claimed scope. The examples do not include representative working embodiments for bacterial antigens, parasitic antigens, fungal antigens, or cancer antigens. The examples also do not establish that the claimed compound would function as an adjuvant across inactivated vaccines, live attenuated vaccines, subunit vaccines, mRNA vaccines, DNA vaccines, or other vaccine platforms under diverse routes, formulations, doses, and disease conditions.
For claim 16, the specification does not provide adequate guidance for preparing kits covering the full range of antigens and instructions for treating or preventing infectious disease or cancer. The claim encompasses kits for an extremely broad set of disease indications and antigen types. However, the specification does not reasonably teach how to select appropriate antigens for all such infectious diseases and cancers, how to pair those antigens with the claimed compound, how to formulate the components, how to determine effective amounts, or how to provide instructions sufficient to treat or prevent the full range of claimed diseases.
This absence of guidance is material because, as taught by Coffiman , Pasquale, Schmidt and Sarker, vaccine adjuvant activity depends on antigen identity, formulation, route of administration, biodistribution, vaccine platform, and desired immune response. Likewise, as taught by Melief, cancer vaccine performance depends on antigen selection, dendritic environment. The specification does not provide a generalizable teaching that would allow a person of ordinary skill to bridge these variables across the full scope of claims 11-13, and 16.
The quantity of experimentation necessary
Given the breadth of the claims, the limited predictability of the art, and the absence of
sufficient guidance and representative working examples, a person having ordinary skill in the art would be required to engage in extensive experimentation to practice the full scope of claims 11-13, and 16.
For claim 11-13, such experimentation would include (1) identifying which antigens within the broad classes of cancer, viral, bacterial, parasitic, and fungal antigens can be effectively combined with the compound of claim 1, (2) determining whether the compound functions as an adjuvant for each antigen, (3) selecting appropriate vaccine platforms, (4) optimizing formulation, dose, route of administration, and immunization schedule, (5) measuring relevant humoral, cellular, and protective immune endpoints, and/or (6) confirming safety and immunogenicity for the relevant infectious disease or cancer context.
For claim 16, such experimentation would further include (1) determining which antigen/ compound combination are suitable for inclusion in a kit, (2) determining effective amounts and formulations for the compound and antigen, (3) identifying instructions sufficient for treating or preventing each covered infectious disease or cancer, and/or (4) confirming that the kit can be used for the claimed therapeutic or prophylactic purpose across the broad range of diseases and antigen types encompassed by the claim.
These experimentations would not be routine verification of a predictable result. As taught by Coffiman , Pasquale, Schmidt, and Sarkar, adjuvant performance depends on multiple interrelated vaccine variables, including antigen identity, vaccine platform, formulation, delivery route, biodistribution, and immune endpoint. As taught by Melief, cancer vaccine performance further depends on tumor antigen selection, dendritic cell activation, T-cell priming and survival, and the tumor immune microenvironment. Therefore, a person of ordinary skill would need to conduct substantial screening, formulation development, immunogenicity testing, challenge studies, cancer/pathogen specific efficacy studies, and safety evaluations to determine which embodiments within the broad claim scope actually work.
Accordingly, the claims 11-13, and 16 do not comply with the enablement requirement of §112, because practicing the claimed invention would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success.
Claim Rejections - 35 USC § 112, second paragraph
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.
The rejections under this section are made when the scope of the claimed subject matter is not clear. (See MPEP 2173)
Claims 1, 11-13, and 16 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance,
claim 1 recites the broad recitation “heterocycloalkyl”, and the claim also recites “morpholine or piperazine” which is the narrower statement of the range/limitation.
claim 11 recites the broad recitation “Adjuvant for a vaccine”, and the claim also recites “an inactivated vaccine, live-attenuated vaccine, subunit vaccine, nucleic acid vaccine such as mRNA or DNA vaccine” which is the narrower statement of the range/limitation. Further, claim 11 recites the broad recitation "nucleic acid vaccine", and the claim also recites "mRNA or DNA vaccine" which is the narrower statement of the range/limitation.
claim 13 recites the broad recitation "HIV antigen, an influenza antigen, and a coronavirus antigen", and the claim also recites "HCOV- 229E, HCOV-OC43, SARS-COV, HCOV-NL63, HCOV-HKU1, MERS-COV, Varicella-zoster virus (VZV) and SARS-COV-2 such as SARS-CoV-2 Omicron mutant, preferably SARS-CoV-2 RBD-Fc protein or gE protein of Varicella zoster virus" which is the narrower statement of the range/limitation. Further, claim 13 recites the broad recitation "SARS-COV-2", and the claim also recites "SARS-CoV-2 Omicron mutant, preferably SARS-CoV-2 RBD-Fc protein or gE protein of Varicella zoster virus" which is the narrower statement of the range/ limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 12 and 16 depend directly from claim 11 and 1, respectively, and are indefinite for the same reason.
Claim Rejections - 35 USC § 112, fourth paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11-13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 depends from claim 1 and recites that the compound of claim 1 or pharmaceutically acceptable salts thereof for use as an adjuvant. The phrase “for use as an adjuvant” merely states an intended use of claim 1, and does not further limit the compounds of claim 1. The claim dose not clearly set forth whether additional structural feature, component, property, formulation, amount, or other limitation that further limits the compound itself. (see MPEP 2114) Accordingly, the metes and bounds of claim 11 is unclear and the claims fail to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claims 12-13 as the dependent claims from claim 11 are rejected under 35 USC 112(b) as indefinite for at least the same reasons set forth above.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-3, and 11-13 is/are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being Slassi et al. by US 2020/0031825 A1 (pub’d 01/30/2020).
With respect to claim 1, the claim recites that a compound having formula (I) or pharmaceutically acceptable salts thereof. Slassi’s compound T (claim 16) falls within the scope of claim 1 as R1 is -O(CH2)3-piperazine, R2 and R3 are N, and R4 and R5 are NH.
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Instant Formula (I) Slassi’s compound T
With respect to claim 2, claim recites that specific compounds of claim 1 or pharmaceutically acceptable salts thereof. Slassi’s compound T corresponds to the second compound in claim 2.
With respect to claim 3, claim recites that a pharmaceutical composition, comprising the
compound of claim 1 or pharmaceutically acceptable salts thereof, and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent. Slassi teaches a pharmaceutically acceptable excipient (paragraph [0192]), a pharmaceutically acceptable carrier (paragraph [0203]), and a pharmaceutically acceptable diluent ((paragraph [0195]) for the compounds or pharmaceutically acceptable salts thereof.
With respect to claims 11-13, claims recites that the compound of claim 1 or pharmaceutically acceptable salts thereof for use as an adjuvant, preferably wherein the adjuvant is an adjuvant for a vaccine preferably wherein the vaccine is an inactivated vaccine, live-attenuated vaccine, subunit vaccine, nucleic acid vaccine such as mRNA or DNA vaccine, and further identifies the vaccine and antigen.
Slassi discloses heteroaromatic fused imidazolyl amide compounds and their use as STING agonists. Slassi further discloses the same compound as recited in claim 1 and 2 or a compound meeting each and every structural limitation of claim 1. Under the claim interpretation, the claims 11-13 merely recite an intended use of the compound of claim 1 and do not impose any additional structural limitation. Under MPEP 211.02, such intended use language does not distinguish the claimed product from the prior art unless it results in a structural difference. Further, under MPEP 2122, a reference that identically discloses the claimed compound may anticipate the claim even if no utility is disclosed. Because the reference discloses the same compound recited in claim 1, and claims 11-13 add only non-limiting intended use language, claims 11-13 are anticipated under MPEP 2131.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Although the claims 11-13, and 16 are rejected under 35 USC 112 for lack of enablement, this 35 USC 103 rejection applies to the enabled scope of the claimed subject matter that can reasonably understood by specification. In addition, the following prior art rejection is made in the alternative to the rejection of claims 1-3, and 11-13 under 35 USC 102.
Claim(s) 1, and 11-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Slassi et al. (US 2020/0031825 A1, pub’d 01/30/2020), Hanson et al. (Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants, J. Clin. Invest., 125(6), 2532-2546, pub’d 05/04/2015), and in further view of Luo et al. (Enhancing Immune Response and Heterosubtypic Protection Ability of Inactivated H7N9 Vaccine by Using STING Agonist as a Mucosal Adjuvant, Front Immunol., 10, 2274, pub’d 09/27/2019).
With respect to claim 11, the claim recites that the compound of claim 1 or pharmaceutically acceptable salts thereof for use as an adjuvant, preferably wherein the adjuvant is an adjuvant for a vaccine preferably wherein the vaccine is an inactivated vaccine, live-attenuated vaccine, subunit vaccine, nucleic acid vaccine such as mRNA or DNA vaccine.
Slassi teaches compounds corresponding to the compound recited in instant claims 1-3, as set forth in the rejection under 35 USC 102 (a)(1)/(a)(2), and those teachings are incorporated by reference herein. Slassi further teaches that STING agonist compounds may be useful in treating infectious disease and cancer (abstract).
Slassi fails to teach use of the particular STING agonist compound of claim 1 in the specific vaccine types recited in claim 11.
Hanson teaches that cyclic dinucleotides are STING agonists and have potential as vaccine adjuvants (abstract). Hanson further teaches that (1) nanoparticulate delivery of a cyclic dinucleotide STING agonist redirects the adjuvant to draining lymph nodes and improves adjuvant performance (introduction and discussion section), (2) nanoparticulate STING agonist delivery promotes durable antibody titers and reduces systemic toxicity compared with unformulated cyclic di-GMP (abstract and results, and discussion section), and (3) such delivery safely targets cyclic dinucleotides to draining lymph nodes and enhances adjuvant efficacy (Nanoparticle delivery of cdGMP enhances expansion of helper T cells and promotes germinal center induction section, and Fig.1).
The combination of Slassi and Hanson fails to teach use of the STING agonist compound in an inactivated influenza viral vaccine.
Luo teaches use of STING agonist as a vaccine adjuvant in an inactivated viral vaccine (abstract). Specifically, Luo further teaches that (1) cGAMP, a STING agonist, is used as a mucosal adjuvant with an inactivated H7N9 influenza vaccine and enhanced humoral, cellular, and mucosal immune response (abstract and discussion section), and (2) the cGAMP combined nasal inactivated influenza vaccine was a promising strategy for broad spectrum influenza vaccines (discussion section).
It would have been obvious to a PHOSITA at the time of the invention to use the STING agonist compound taught by Slassi as a vaccine adjuvant in an inactivated viral vaccine, such as the inactivated influenza vaccine taught by Luo. Slassi teaches STING agonist compounds and their use in treating infectious diseases and cancer. Hanson teaches that STING agonists are potent vaccine adjuvants and provide advantages including lymph node targeted delivery, enhanced adjuvant efficacy, durable antibody titers, and reduced systemic toxicity. Luo teaches that use of a STING agonist adjuvant in an inactivated H7N9 influenza vaccine enhances humoral, cellular, and mucosal immune responses and provides a promising strategy for broad spectrum influenza vaccines. It would have been motivated to combine these teachings to use the STING agonist compound of Slassi as a vaccine adjuvant, as taught by Hanson, in an inactivated influenza viral vaccine, as taught by Luo, to obtain the predictable advantages taught by Hanson, and Luo, including enhanced adjuvant efficacy, improved immune responses, durable antibody titers, reduced systemic toxicity, and broader influenza protection (discussion section).
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A) in the claim 11, it would have been prima facie obvious to combine the STING agonist compound taught by Slassi as a vaccine adjuvant, including in an inactivated viral vaccine such as the inactivated influenza vaccine taught by Luo, because combining STING agonist compounds known to function as treating infectious diseases and cancer, and vaccine adjuvants with vaccine formulations known to benefit from STING agonist adjuvant activity represents the predictable use of known elements according to their established functions, yielding predictable results, including enhanced adjuvant efficacy, improved immune responses, durable antibody titers, reduced systemic toxicity, and broader influenza protection. (see MPEP 2141)
With respect to claim 12, the claim recites that the compound or pharmaceutically acceptable salts thereof for the use according to claim 11, wherein the vaccine comprises an antigen selected from a group consisting of a cancer antigen, a viral antigen, a bacterial antigen, a parasitic antigen, and a fungi antigen.
Slassi teaches one or more compounds of the application are coupled to an antibody to form an
antibody-drug conjugate, and the antibody targets an antigen that is specific to a type of cancer or tumor (paragraph [0012]).
However, Slassi and Hanson fail to teach the vaccine comprises an antigen selected from a group consisting of a cancer antigen, a viral antigen, a bacterial antigen, a parasitic antigen, and a fungi antigen.
Luo teaches that an inactivated H7N9 influenza vaccine (i.e., a viral antigen containing vaccine) is combined with cGAMP as a STING agonist mucosal adjuvant (cGAMP Adjuvanted Vaccine Induces
Improved Cross Protection Against a Lethal Dose Challenge of the Heterosubtypic Virus section). Luo further teaches that the combination enhanced humoral, cellular, and mucosal immune responses and provided heterosubtypic protection (discussion section).
With respect to claim 13, the claim recites that the viral antigen is selected from a group consisting of an HIV antigen, an influenza antigen, and a coronavirus antigen, preferably an antigen from one or more of, HCOV- 229E, HCOV-OC43, SARS-COV, HCOV-NL63, HCOV-HKU1, MERS-COV, Varicella-zoster virus (VZV) and SARS-COV-2 such as SARS-CoV-2 Omicron mutant, preferably SARS-CoV-2 RBD-Fc protein or gE protein of Varicella zoster virus.
Slassi teaches a STING agonist compounds as discussed above, and Hanson teaches use of a STING agonist adjuvant in connection with antigen specific vaccine responses and specifically includes an HIV gp41 peptide antigen vaccine context (abstract and results section). Therefore, Hanson teaches use of STING agonist adjuvants with an HIV antigen. Hanson also teaches advantages of STING agonist adjuvant delivery, including enhanced adjuvant efficacy, improved immune responses, durable antibody titers, reduced systemic toxicity, and broader influenza protection (discussion section).
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Slassi et al. (US 2020/0031825 A1, pub’d 01/30/2020), Hanson et al. (Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants, J. Clin. Invest., 125(6), 2532-2546, pub’d 05/04/2015), and Luo et al. (Enhancing Immune Response and Heterosubtypic Protection Ability of Inactivated H7N9 Vaccine by Using STING Agonist as a Mucosal Adjuvant, Front Immunol., 10, 2274, pub’d 09/27/2019), as applied to claim 1 and 11-13 above, and further in view of Fu et al. (STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade, Sci. Transl. Med., 7(283), 283ra52, pub’d 4/15/2015).
With respect to claim 16, the claim recites that a kit comprising the compound of claim 1, an antigen, and instructions for treating or preventing an infectious disease or a cancer.
Slassi teaches STING agonist compounds and their use in treating infectious diseases and cancer. Hanson teaches that STING agonists are potent vaccine adjuvants and provide advantages including lymph node targeted delivery, enhanced adjuvant efficacy, durable antibody titers, and reduced systemic toxicity. Luo teaches that use of a STING agonist adjuvant in an inactivated H7N9 influenza vaccine enhances humoral, cellular, and mucosal immune responses and provides a promising strategy for broad spectrum influenza vaccines.
The combination of Slassi, Hanson, and Luo fail to teach a kit comprising the SYING agonist compound, an antigen, and instructions for treating or preventing an infectious disease or a cancer.
Fu teaches STING agonist formulated cancer vaccines, and STING agonist formulated vaccines induce antitumor immunity and that such vaccines can treat established tumors, including tumors resistant to PD-1 blockade (abstract and results section). Therefore, Fu provides an additional cancer vaccine teaching relevant to the claim 16 requiring instructions for treating or preventing cancer.
Providing a pharmaceutical compound in a container as a kit would have been a conventional and predictable way to store, preserve, transport, and dispense the compound for its intended pharmaceutical use. Providing the containerized STING agonist compound together within instructions for use as a vaccine adjuvant would have merely involved arranging known components according to their established functions to facilitate the known and predictable combined use of the STING agonist compound with a vaccine or antigen. Moreover, to the extent the kit includes instructions for use, such instructions merely describe the intended use of the known components. The instructions do not create a new structural of functional relationship between the container, the STING agonist compound, and the vaccine or antigen, nor do they change the established functions of those components. Therefore, the claimed kit, including the container and instructions, does not patentably distinguish the claim from the prior art components provided together for their known and predictable combined use. (see MPEP 2143 and 2111.05)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to provide the STING agonist compound taught by Slassi, together with an antigen and instructions for treating or preventing an infectious disease or cancer, in the form of a kit. Slassi teaches the relevant STING agonist compounds and their use for treating infectious disease and cancer, and Hanson teaches the motivation to use STING agonists as vaccine adjuvants to obtain improved lymph node targeting, enhanced adjuvant efficacy, durable antibody titers, and reduced systemic toxicity. Further, Luo teaches that a STING agonist adjuvant within an inactivated influenza antigen improves immune responses and heterosubtypic protection agonist influenza, and Fu teaches that STING agonist formulated cancer vaccines can treat established tumor, including tumors resistant to PD-1 blockade. A person of ordinary skill in the art would have been motivated to combine these teachings to provide a kit containing Slassi’s STING agonist compound and an antigen together with instructions for use the combination in a vaccine setting. The motivation would have been to obtain the predictable advantages including enhanced adjuvant efficacy, durable antibody titers, and reduced systemic toxicity taught by Hanson, enhanced humoral, cellular, and mucosal immune responses and broader influenza protection taught by Luo, and antitumor vaccine activity against established cancer taught by Fu.
Additionally, applying KSR example rationale (A) in the claim 16, it would have been prima facie obvious to provide the STING agonist compound taught by Slassi with an antigen and instructions for treating or preventing cancer in the form of a kit, because combining STING agonist compounds known to function as vaccine adjuvants with antigens and instructions for known cancer vaccine or immunotherapy uses represents the predictable use of known elements according to their established functions, yielding predictable results. (see MPEP 2141)
Art of Record but not Applied
As discussed above, the kit and instructions limitation would have been obvious. These limitations do not create a new structural or conditional relationship between the STING agonist compound, the container, and the antigen. Alternatively, EP3785719A1 provides further support because it teaches a kit comprising a cyclic dinucleotide adjuvant together with an antigen vaccination component for using for preventing and treating infectious diseases as promoting an immune response in prophylactic or therapeutic vaccination.
Conclusion
Claims 1-3, 11-13, and 16 are rejected.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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