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 .
Claims 1-27, submitted on 5 April 2023, represent all claims currently under consideration.
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.
Priority
This application is a 371 of PCT/EP2021/07727, filed 7 October 2021, which claims priority to provisional US 63/160,768, filed 13 March 2021, and provisional US 63/088,652, filed 7 October 2020. This application also claims priority to FR 2105065, filed 12 May 2021, and EP 21174850.4, filed 19 May 2021. All claims are supported in US 63/088,652. The effective filing date is 7 October 2020.
Information Disclosure Statement
Three Information Disclosure Statements (IDSs), submitted on 5 April 2023 and 27 April 2023 (2), are acknowledged and have been considered.
Specification
The spacing of the lines of the specification is such as to make reading difficult. New application papers with lines 1 1/2 or double spaced (see 37 CFR 1.52(b)(2)) on good quality paper are required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (Page 11, Line 30). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim states “comprises comprising”. The extra “comprising” should be removed. Appropriate correction is required.
Claims 2, 18, and 19 are objected to because of the following informalities: The definitions for variable R are provided multiple times, which is not necessary. Appropriate correction is required.
Claims 2, 18, and 19 are objected to because of the following informalities: The images of Compounds (I), (II), (III), (VI), and (VII) are low quality and are difficult to interpret. Appropriate correction is required.
Claim 12 is objected to because of the following informalities: “N-acetyl-cystein” should be “N-acetyl-cysteine”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: The claim reads “elevated markers inflammation”. The Examiner believes this should read “elevated markers of inflammation”. Appropriate correction is required.
Claim 27 is objected to because of the following informalities: The claim reads “release or other biomarkers”. The Examiner believes this should read “release of other biomarkers”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 2 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
The claims are directed towards methods and compositions for inhibiting caspases, with one compound claimed being of structure
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(Formula VII), and the similar compound of Formula (VI)
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. However, the specification does not provide a single specific compound of these formulas, nor does the specification provide any tests demonstrating that these compounds can be used in the methods as claimed. There are no methods of synthesizing these compounds provided. There is no predictability of success for the artisan as there is no representative compound provided, no demonstration of utility of these compounds as inhibitors of caspases, and no method of producing these compounds. Therefore, there is no support in the specification that would lead one of ordinary skill in the art to recognize that applicant was in possession of the claimed invention as a whole at the time of filing.
Claims 1, 17 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
The claims are directed towards methods and compositions of treating disease comprising an inhibitor of inflammatory caspases. There is no general structure provided for these compounds, and are only described by their function (inhibitors of inflammatory caspases characterized in that it selectively or preferentially inhibits at least one or all of the so-called inflammatory caspases including human Caspase-1, human Caspase-4, and human Caspase-5). The specification provides specific caspase inhibitors to practice the invention, defined by formulas (I) through (VIII). However, there is no general structure provided which can encompass all known caspase inhibitors, and as the claim only defines these compounds by their function, the artisan would have no reasonable expectation of predictability as they would not know if a compound functioned as a caspase inhibitor until it was tested. There is no support in the specification for the breadth of these claims as the only defined caspase inhibitors are those of formulas (I) through (VIII). Therefore, there is no support in the specification that would lead one of ordinary skill in the art to recognize that applicant was in possession of the claimed invention as a whole at the time of filing.
Claims 1 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
The claims are directed to methods of ameliorating, treating or preventing a variety of specific conditions, as well as diseases associated with excessive activation of the canonic and non-canonic inflammasome, comprising administering an inhibitor of inflammatory caspases. The specification provides support, as well as data, demonstrating the use of specific compounds for the treatment and amelioration of conditions associated with viral respiratory infections such as COVID-19 and MERS. However, there is no further support provided in the specification that describes the treatment of “diseases associated with excessive activation of the canonic and non-canonic inflammasome”. This encompasses an exceedingly broad class of diseases and conditions, such as various autoimmune conditions, diabetes, neurodegenerative disorders, and cancer. There are no examples provided demonstrating the use of caspase inhibitors for the treatment of conditions other than those associated with viral infections. The artisan would have no predictability in treating all diseases associated with excessive activation of the canonic and non-canonic inflammasome as these conditions require specific methods of treatment, and there is no indication from the specification that these compounds are useful for the treatment of all conditions associated with excessive activation of the inflammasome. There is no support in the specification for the breadth of the claims. Therefore, there is no support in the specification that would lead one of ordinary skill in the art to recognize that applicant was in possession of the claimed invention as a whole at the time of filing.
Claim 27 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
The claim is directed to a method of reduction of the release of biomarkers in a patient having a coronavirus infection or other respiratory viral infections. The specification defines “biomarker” as a physical, functional or biochemical indicator, e.g., the presence of a particular metabolite, of a physiological or disease process. Certain biomarkers of inflammation may be used to evaluate the response of patients having coronavirus infection, cytokine release syndrome, or cytokine storm syndrome to inhibitor of inflammatory caspases. These biomarkers include, but are not limited to, IL-1β, activated caspase-1, cleaved caspase-1, cleaved IL-18, IL-6, IL-10, IL-4, LDH, and C-reactive protein (Page 45, Lines 23-29). The biomarkers which can be reduced during the treatment of COVID-19 or similar infections are numerous, and would include other inflammatory markers such as TNFα, growth factors, procalcitonin, markers of coagulation such as D-dimer levels, fibrinogen, fibrin degradation products, hepatic markers such as AST, ALT, bilirubin, and albumin, renal markers such as serum creatinine, and electrolytes such as levels of calcium, sodium, and potassium. There are no data provided in the specification demonstrating that the methods as described will predictably result in a reduction in the release of all biomarkers associated with COVID-19 or other viral respiratory infections. The artisan would generally recognize and know that treatment with a caspase inhibitor would result in the reduction of the activity of caspases, maturation of IL-1β and release, IL-1α release, IL-18 maturation, and pyroptosis, but would not have any predictability for the reduction of the release of all biomarkers in a patient suffering from the claimed conditions. The breadth of these biomarkers is immense, and there is no evidence provided in the specification that these methods can be used to reduce the release of all known biomarkers in a patient suffering from COVID-19. The treatment of complex diseases which impact multiple organ systems such as COVID-19 is highly unpredictable, and the use of a caspase inhibitor would not be expected to result in the reduction of all known biomarkers associated with this disease. There is no support in the specification for the breadth of the claim. Therefore, there is no support in the specification that would lead one of ordinary skill in the art to recognize that applicant was in possession of the claimed invention as a whole at the time of filing.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 17 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. Claims 1 and 17 read “inhibits at least one or all of the so-called inflammatory caspases including human caspase-1, human caspase-4, and human caspase-5”. 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, claims 1 and 17 recite the broad recitation “inhibits at least one or all of the so-called inflammatory caspases”, and the claim also recites “including human Caspase-1, human Caspase-4, and human Caspase-5” 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 2-16 and 18-27 are rejected as dependent upon an indefinite claim without resolving the underlying issue of definiteness.
Claims 2 and 18 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, claims 2 and 18 recite the broad recitation of the compound of Formula (I), and the claim also recites the compound of Formula (V), also known as Belnacasan which is the narrower statement of the range/limitation. The claims 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 2 and 18 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, claims 2 and 18 recite the broad recitation compounds of formula (I) and formula (III), and the claim also recites the specific stereoisomer (II) and (IV) which is the narrower statement of the range/limitation. The claims 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 2 and 19 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, claims 2 and 19 recites the broad recitation Compound (VII), and the claim also recites Compound (VI) 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.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim states “ a pharmaceutical composition comprising either entity”. There are more than two compounds which are claimed in Claim 2, which renders the claim indefinite because it is not clear which two compounds are included in the “either entity”.
Claims 3 and 20 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, claims 3 and 20 recites the broad recitation “parenteral”, and the claim also recites intravenous and other parenteral routes of administration, 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.
Claim 12 is 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. There is no “or” or “and” at the end of the Markush group of second active ingredients rendering the claim indefinite.
Claims 13 and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim reads the method of Claim 1 composing “administering an antibiotic or several antibiotics”. It is unclear what “several antibiotics” encompasses. There is no definition of “several” in the specification, rendering it unclear how many antibiotics can be administered for this method.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The phrase “ the SARS-Cov-2” lacks antecedent basis.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim reads “..or rectal route”. It is unclear if this single composition can be administered through all routes in the same formulation, or if there are specific formulations for each route of administration. The Examiner suggests changing the “or” to an “and”.
Claim 25 is 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 25 recites the broad recitation “SARS-CoV-2 protease inhibitor”, and the claim also recites “PF-07321332 and PF-07304814” which is the narrower statement of the range/limitation. The claims 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.
Claim Rejections - 35 USC § 112(d)
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 3 and 20 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. Claims 3 and 20 claim a composition which can be administered to the patient by oral, parenteral, intravenous, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal route. These claims do not further limit the parent claim because these are the only routes of administration which can be utilized (Parenteral encompasses all routes of administration that do not enter the GI system). 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
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 17, 18, and 20-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wannamaker (US Patent No. 7,417,029; Patent Date: 26 August 2008).
Wannamaker (See IDS, 5 April 2023) discloses an IL-1β converting enzyme (ICE) inhibitor prodrug of structure
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(Abstract). ICE is also known as Caspase-1. The compound is a prodrug that undergoes bioconversion to an active ICE inhibitor
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(Column 5, Lines 34-50). Pharmaceutical compositions of this invention comprise a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may optionally comprise an additional therapeutic agent. Such agents include, but are not limited to, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin, or an anti-vascular hyperproliferation compound (Column 8, Lines 45-54). Wannamaker discloses a composition containing a caspase-1 inhibitor which is identical Formula (V), optionally with a second therapeutic agent. The claims as written are directed to a pharmaceutical composition comprising a caspase-1 inhibitor. The “for ameliorating, treating or preventing” limitations are intended use; a recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. As the compositions of Wannamaker are capable of performing the intended use, these compositions meet the limits of the claims (See MPEP § 2112.02 (II)).
Claims 1-3, 5, 14, 15, 17, 28, 20-24, and 27 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rawtert (WO 2021/185912; Publication Date: 23 September 2021; Priority to 19 March 2020).
Rawtert (See IDS, 5 April 2023) provides a method of treatment of a NLRP-3 associated disease or condition in a subject, the method comprising administering a medically active liquid in nebulized form wherein the medically active liquid comprises a NLRP3 inhibitor (Abstract). The NLR protein recruits the inflammasome-adaptor protein ASC, which in turn interacts with caspase-1 leading to its activation. Once activated, caspase-1 promotes the maturation of the pro-inflammatory cytokines interleukin IL-1β and IL-18 (Page 1, Line 31-Page 2, Line 2). The medically active liquids for use, methods or uses according to the present invention allows for the treatment or prevention, preferably for the treatment of a viral infection in a patient or subject. Such viral infections may be selected from a broad variety of infections including coronavirus, influenza virus, rhinovirus, and adenovirus, such as SARS viruses, MERS viruses, H1N1 influenza, and Avian Flu H5N1, specifically severe acute respiratory syndrome viruses (SARS) such as SARS-CoV or SARS-CoV-2, and MERS-CoV (Page 9, Line 25- Page 10, Line 2). In further specific embodiments, the viral infection to be treated or prevented is a severe acute respiratory syndrome (SARS), more specifically a SARS-CoV or SARS-CoV-2 virus infection (Page 10, Lines 7-9). In further specific embodiments, the subject is diagnosed with COVID-19 (Page 10, Line 31). The NLRP3 inhibitor can be selected from the group which includes VX-765 (Belnacasan) (Page 45, Embodiment 24). The medically active liquid can further comprise at least one further medically active compound (Page 45, Embodiment 25).
Rawtert discloses a composition containing the caspase inhibitor Belnacasan, optionally with a second therapeutic agent. The claims as written are directed to a pharmaceutical composition comprising a caspase-1 inhibitor. The “for ameliorating, treating or preventing” limitations are intended use; a recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. As the compositions of Rawtert are capable of performing the intended use, these compositions meet the limits of the claims (See MPEP § 2112.02 (II)).
Claims 1-11, 14-18, 20-24, and 27 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Alpan (WO 2021/211659; Publication Date: 21 October 2021; Priority to 14 April 2020).
Alpan (See IDS, 5 April 2023) discloses the use of caspase inhibitors to treat COVID-19 patients or individuals at risk of infection by limiting the malfunction of the immune system. A caspase-1 or pan-caspase inhibitor is advantageously administered before or very early in the course of infection by a positive-sense, single stranded RNA virus such as SARS-CoV, MERS-CoV, or SARS-CoV2 (Abstract). One pan-caspase inhibitor that can be used in the methods of the invention is Emricasan (Paragraph 79). The pharmaceutical compositions of the invention contain therapeutically effective amounts of one or more caspase inhibitors and a pharmaceutically acceptable carrier. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a particular mode of administration (Paragraph 80). Dosages are described which encompasses those which are claimed (Paragraph 83). Compositions containing caspase inhibitors are intended to be administered by a suitable route, including orally, parenterally, rectally, topically, locally, by inhalation spray, nasally, buccally, vaginally, by an implanted reservoir, or via nasogastric or orogastric tube (Paragraph 85). The compounds provided herein can be administered to a subject having a condition modulated by one or more caspases together with another pharmacological agent known in the art to be of value in treating the same condition (Paragraph 88). The compounds of the invention can be administered alone or in combination with one or more antiviral agents (Paragraph 111). Treatment of COVID-19 according to the invention includes the administration of a caspase inhibitor to a patient at any level of COVID-19 severity (Paragraph 121). The caspase inhibitor to be used in the claimed methods can be selected from Emricasan, CTS-2090, Belnacasan (VX-765), Pralnacasan (VX-740), and O-desethyl-belnacasan (VRT-043198) (Claim 7).
Alpan discloses a composition containing the caspase inhibitor Belnacasan, optionally with a second therapeutic agent. The claims as written are directed to a pharmaceutical composition comprising a caspase-1 inhibitor. The “for ameliorating, treating or preventing” limitations are intended use; a recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. As the compositions of Alpan are capable of performing the intended use, these compositions meet the limits of the claims (See MPEP § 2112.02 (II)).
Claims 1-11, 17, 18, 20-24, and 27 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fishbein (WO 2021/2226897; Publication Date: 4 November 2021; Priority to 1 May 2020).
Fishbein (See IDS, 5 April 2023) discloses methods for treating COVID-19 by targeting the inflammasome/caspase1/pyroptosis axis as a key inflammatory pathway. The invention relates to treating a patient infected with SARS-CoV-2 with an effective amount of one or more compounds that directly or indirectly inhibit one or more pathways of the inflammasome/caspase 1/pyroptosis axis (Abstract). Inhibitors of the inflammasome of the invention include VX-765 (Paragraph 0053). VX-765 is advantageously formulated as a solution or a tablet. The dosage may be about 10 to 100 mg/kg. A tablet of VX-765 may be about 300 mg per tablet with daily dosage of about 900 mg to about 3600 mg (Paragraph 0062). The pharmaceutical composition of the present invention may be administered in combination with another therapeutic agent, advantageously one used for COVID-19 (Paragraph 0067). Vitamin supplementation enhances immune response: Vitamin A, D, E, and C, selenium and zinc. The above supplements have a variety of effects including immune modulation, particularly vitamin D, improving recovery from viral infections (Paragraph 0069). Antivirals can be used with this invention (Paragraph 0073). Pharmaceutical compositions of the invention may comprise a compound of VX-765 or any other caspase 1/ICE inhibitor and a pharmaceutically acceptable carrier. Such compositions may comprise an additional therapeutic agent, including but not limited to an anti-inflammatory agent, MMP inhibitor, lipoxygenase inhibitor, cytokine antagonist, immunosuppressant, anti-cancer agent, anti-viral agent, cytokine, growth factor, immunomodulator, prostaglandin, or anti-vascular hyperproliferation compound (Paragraph 0089). The pharmaceutical compositions of this invention may be administered orally, parenterally, inhalation, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir (Paragraph 00101). Dosages levels of between 0.01 and 100 mg/kg body weight per day are useful for the prevention and treatment of conditions (Paragraph 00107).
Fishbein discloses a composition containing the caspase inhibitor Belnacasan, optionally with a second therapeutic agent. The claims as written are directed to a pharmaceutical composition comprising a caspase-1 inhibitor. The “for ameliorating, treating or preventing” limitations are intended use; a recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. As the compositions of Fishbein are capable of performing the intended use, these compositions meet the limits of the claims (See MPEP § 2112.02 (II)).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-12, 17-19, 20-25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Fishbein (WO 2021/2226897; Publication Date: 4 November 2021; Priority to 1 May 2020) in view of Thomas (WO 2011/094426; Publication Date: 4 August 2011).
The teachings of Fishbein are described previously and fully incorporated into this rejection.
Fishbein fails to teach the use of compound of Formula (VIII) in the claimed methods.
Thomas compounds that function as caspase inhibitors (Abstract). Embodiment 13 discloses the compound
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and is further claimed in Claim 14. This compound is identical to compound (VIII), and is referred to as NCGC00183434 or compound 4. This compound has an IC50 against caspase 1 of 0.023 nM (Table 1, Figure 7).
Fishbein and Thomas are considered analogous to the claimed invention as all are involved in the use of caspase inhibitors for the treatment of disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to substitute compound 4 of Thomas in place of the caspase inhibitor of Fishbein, and further apply this compound for the treatment of COVID-19. This substitution is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Fishbein discloses a method of treating COVID-19 using caspase-1 inhibitors, while the compound of Thomas is a potent caspase-1 inhibitor. The artisan would recognize this, and by substituting this compound in place of the methods of Fishbein, would predictably arrive at a method for the treatment of COVID-19. The artisan would have a motivation and reasonable expectation of success in picking this specific compound due to the data provided which demonstrate that it is a potent inhibitor of caspase-1.
Claims 1-27 are rejected under 35 U.S.C. 103 as being unpatentable over Fishbein (WO 2021/2226897; Publication Date: 4 November 2021; Priority to 1 May 2020) in view of Thomas (WO 2011/094426; Publication Date: 4 August 2011), Cheng (Antiviral Research, 100, 2013, 407-419), Rangel-Mendez (Future Microbiology, 14 July 2020, 15(11), 959-962), and Adam (Critical Care, 24 September 2020, 24:574).
The teachings of Fishbein and Thomas are described previously and are fully incorporated into this rejection.
Fishbein and Thomas fail to teach the further use of antibiotics, N-acetyl cysteine, fibrin-derived peptide Bβ-15-42 (FX06), molnupiravir or a SARS-CoV-2 protease inhibitor.
Cheng provides a review of treatment strategies applied during the SARS outbreak of 2003. At the time of the outbreak, there were no known effective antiviral agents for SARS; as such, supportive care and the use of broad-spectrum antibiotics to cover secondary bacterial infections were the key treatment regimen (Page 408). Patients were given antibiotics for the treatment of community-acquired pneumonia, with coverage of both typical and atypical bacterial pathogens. Broad spectrum antibiotics were indicated in patients who developed nosocomial bacteremia, catheter-related sepsis and nosocomial pneumonia due to E. coli, K. pneumoniae, and S. maltophilia (Page 409).
Rangel-Mendez discusses the use of N-acetylcysteine as a potential treatment, preventative, and/or adjuvant against SARS-CoV-2. NAC exhibits a mucolytic effect due to its free sulfhydryl group which reduces disulfide bonds in the cross-linked mucus glycoproteins matrix, thereby lowering mucus viscosity and it is a potent antioxidant with direct effect on certain oxidant species, an direct effect because it acts as a precursor to cysteine (required for glutathione synthesis), and the ability to restore thiol pools which in turn regulate redox state (Page 959). In vitro studies have shown NAC to block ACE, which may provide protection from the deleterious effects of angiotensin II, a potentially useful activity in a SARS-Cov-2 infection scenario. The oxidative stress environment created by cytokine storm syndrome and production of reactive oxygen species may be attenuated by NAC’s antioxidant effect (Page 960).
Adam reports on the use of FX06 in critically ill patients suffering from COVID-19. They observed substantial improvement in lung function following administration of FX06, which may be attributed to its immunomodulatory properties and its function to preserve the endothelial barrier. Patients treated with FX06 displayed remarkable increase of their oxygenation indices, likely due to normalization of the pulmonary vascular walls. Levels of IL-6 were further seen to be decreased in the patients. Based on their experience, the use of FX06 in severe COVID-19 associated ARDS could be an effective therapy to improve pulmonary function and vascular leakage in the most severely ill patients.
Fishbein, Thomas, Cheng, Rangel-Mendez, and Adam are considered analogous to the claimed invention as all are involved in the treatment of human disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to include antibiotics, N-acetylcysteine, or FX06 in conjunction with caspase-1 inhibitors for the treatment of COVID-19 or similar respiratory viral infections. The prior art of Cheng, Rangel-Mendez, and Adam each demonstrate that these therapeutics are useful in the treatment of SARS and/or SARS-CoV-2 infections. Similarly, Vitamin D, molnupiravir and SARS-CoV-2 protease inhibitors are known to be useful in the treatment of these conditions. Thus, their use in combination with other known treatments for these diseases is prima facie obvious combination of equivalents known for the same purpose (See MPEP § 2144.06 I). Each component is known individually to be useful for the treatment of these conditions, thus it would be obvious to the artisan to combine them to form a third composition which would be useful for the same purpose.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 3, 4, 5, 12, 14-17, 20, 21-25, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5, 10-12, and 15-17 of copending Application No. 17/998,512 (Amended Claims of 11 November 2022) (‘512).
Claim 1 is directed to a method of preventing or treating an infection caused by a virus in a subject in need thereof comprising administering a compound of Formula (I)
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. This compound is a caspase inhibitor. Claim 2 claims