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 .
Claim Status
Claims 1-18, 34-58, and 72 are pending. Claims 7-10, 12-14, 16-17, and 38-58 are withdrawn. Claims 1-6, 11, 15, 18, 34-37, and 72 are presently considered.
Election/Restrictions
Applicant’s election without traverse of Group I (products) and the species (or subgenus of patentably indistinct species) of combination of amodiaquine, potassium canrenoate, and exenatide in the reply filed on 08/11/2026 is acknowledged.
The elected species (or subgenus of patentably indistinct species) is understood to be a “combination” of amodiaquine, potassium canrenoate, and exenatide, wherein Example 1 at Group 4M at Table 1 (see Spec. filed 2/16/2024 at page 86) is a “nonlimiting example” of this combination (see, e.g., Reply filed 8/11/2026 at 10). The “nonlimiting example” of the originally elected subgenus of patentably indistinct species is understood to comprise 0.05 µg/kg of exenatide, 0.33 mg/kg of potassium canrenoate, and 20 mg/kg amodiaquine, wherein the formulation is identified as suitable for intravenous injection (see id). Accordingly, because the specific concentrations are a “nonlimiting example”, and the elected combination is of “amodiaquine; potassium canrenoate; and exenatide”, then it is reasonably inferred that Applicant has elected a subgenus of patentably indistinct species of combinations defined by the presence of amodiaquine, potassium canrenoate, and exenatide rather than specific concentration ratios of each component.
Applicant identifies that claims 1-6, 11, 18, 34-39, 44-54, 56-58, and 72 read on the elected combination (see, e.g., Reply filed 8/11/2026 at 10). Upon review, the elected subgenus does not read upon claim 7, because it contains exenatide rather than a “structural or functional analogue of exenatide”; the elected subgenus does not read upon claims 8-10, and 12-14 because it lacks a sulfonylurea (e.g., gliberclamide); the elected subgenus does not read upon claim 16 as it lacks a hydrochloride salt of amodiaquine; and the elected species does not read upon claim 17 as it lacks an additional active pharmaceutical ingredient (API) enumerated therein. However, although Applicant identifies that the elected species does not read upon claim 15, this is mistaken, and claim 15 is presently considered. In addition, although Applicant identifies that the elected species reads upon instant claims 38-39, 44-54, and 56-58, Examiner notes that these claims are directed to a non-elected invention, namely methods, and that the elected species lacks active method steps (see, e.g., Requirement mailed 6/11/2026 at 3-7). Accordingly, the originally elected subgenus of patentably indistinct species is understood to read upon claims 1-6, 11, 15, 18, 34-37, and 72.
Following extensive search and examination, the originally elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1-6, 11, 15, 18, 34-37, and 72 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 38-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/11/2026.
Claims 7-10, 12-14, and 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/11/2026.
Claims 1-6, 11, 15, 18, 34-37, and 72 are presently considered
Priority
The priority claim to GR20210100572 (filed 8/27/2021) and PCT/IB2022/058008 (filed 8/26/2022) are acknowledged.
Information Disclosure Statement
The IDS filed on 2/19/2024 and 9/04/2026 are acknowledged and presently considered.
Applicant should note that one or more documents disclosed on the IDS form submitted on 9/04/2026 were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest priority claim is to GR20210100572 filed 8/27/2021; therefore, all documents published in 2020 or later must be accompanied by both month and date of publication.
References that were not considered have been indicated by strike-though on the attached IDS forms. Although not considered, these documents have been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Specification
Sequence Listing: The instant disclosure is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claims and/or disclosure contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424). Specifically, the instant application discloses sequences at page 16 at lines 15-25.
Appropriate correction is required.
Drawings
The drawings filed 2/16/2024 are accepted.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
1. A combination comprising:
(a) a first component that is a Nurr1 agonist; and
(b) at least one additional component selected from:
(i) an aldosterone antagonist;
(ii) an insulin modulator; and
(iii) a sulfonylurea.
Accordingly, the claims are directed to products (i.e., “a combination”), comprising at least two components. The applicable claim interpretation is discussed below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Combination” is identified on record as encompassing compositions wherein “each of the pharmaceutically active components of the combination . . . is administered separately” and wherein “the components of the inventive combination may be for administration simultaneously, sequentially or separately” (see, e.g.., Spec. filed 2/16/2024 at 68 at line 20 to page 69 at line 32). Accordingly, the claimed invention includes a “combination” that may simply be two or more separate and distinct components (e.g., a kit), wherein the components do not need to be formulated together.
“Nurr1 agonist” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function. Although it is understood that the phrase encompasses at least amodiaquine, chloroquine, glafenine, and hydroxychloroquine (see, e.g.., Spec. filed 2/16/2024 at 8 at lines 1-15), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.).
“Aldosterone antagonist” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function. Although it is understood that the phrase encompasses at least spironolactone, eplerenone, canrenone, potassium canrenoate, finerenone, prorenone, progesterone, drospirenone, gestodene, and benidipine (see, e.g.., Spec. filed 2/16/2024 at 18 at line 29 to page 20 at line 13), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.).
“Insulin modulator” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function:
As used herein the term "insulin modulator" refers to an agent that is capable of directly or indirectly increasing or decreasing the activity of insulin, which in turn may increase or decrease the insulin-mediated physiological response.
(see, e.g., Spec. filed 2/16/2024 at 15 at lines 5-10).
In addition, the genus of “Insulin modulators” is defined by reference to additionally functionally defined genera (e.g., Spec. filed 2/16/2024 at 15 at lines 10-12, reciting “GLP-1 agonists, DPP-4 inhibitors, PPAR agonists”). Although it is reasonably understood that the phrase encompasses at least exenatide and the expressly identified compounds (see, e.g.., Spec. filed 2/16/2024 at 15 at line 13 to page 16 at lines 5), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.).
“Sulfonylurea” is a genus of a known class of agents (see, e.g.., Spec. filed 2/16/2024 at 9 at line 11 to page 14 at line 35).
The phrase “structural or functional analogue” is recited at least at claims 4, 6-7, and 9-15. The Specification identifies that this phrase does not correspond to a particular structure or function:
As used herein, a structural analogue, also known as a chemical analogue, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analogue can be imagined to be formed, at least theoretically, from the other compound.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 1-6).
As used herein, functional analogues are chemical compounds that have similar physical, chemical, biochemical, or pharmacological properties to that of another compound. Functional analogues are not necessarily structural analogues with a similar chemical structure.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 5-10).
Accordingly, the metes and bounds of such phrases and the associated definitions depend upon the arbitrary interpretation of at least what does or does not constitute “similar” to the inventor or an artisan (see also Spec. filed 2/16/2024 at 17 at lines 14-20). For purposes of applying prior art, the phrases are interpreted as including at least the explicitly claimed and recited “structural or functional analogues” enumerated in the pending claims (see, e.g., instant claims 7, 10).
Claims 34-37 recite active method steps (“the combination is formulated for….”), which render the claims indefinite per MPEP § 2173.05(p)(II) (explaining that claims directed to a product that recite method steps utilizing that product are indefinite). For purposes of applying prior art, these claims are interpreted as reciting “the combination is capable of being formulated for”, which is reasonable and would constitute a recitation of intended or expected use. Notably, under such an interpretation, “a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim” (see, e.g., MPEP § 2111.02(II); see also, In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997)).
Amodiaquine is interpreted consistently with the description of record as a “Nurr1 agonist”, and is understood to correspond to the structure
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146
250
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(see, e.g., Spec. filed 2/16/2024 at 8 at lines 1-20).
“Potassium canrenoate” is interpreted consistently with the description of record as a “aldosterone antagonist”, and is understood to correspond to the structure
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167
323
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(see, e.g., Spec. filed 2/16/2024 at 20 at lines 14-30).
“Exenatide” is interpreted consistently with the description of record as an “insulin modulator”, and is understood to correspond to the structure:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala- Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(see, e.g., Spec. filed 2/16/2024 at 16 at lines 5-30).
Additional claim interpretations are set forth below.
Claim Rejections
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 1-6, 11, 15, 18, and 34-37 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.
Claim 1 recites “Nurr1 agonist” which renders the claim scope indefinite. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, “nurr1 agonist” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims. Although it is reasonably assumed that the phrase encompasses at least amodiaquine, chloroquine, glafenine, and hydroxychloroquine (see, e.g.., Spec. filed 2/16/2024 at 8 at lines 1-15), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.). Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not qualify as a “nurr1 agonist” at instant claim 1, an artisan would be unable to identify infringing from non-infringing compounds, commensurate in scope with the instant claim, and therefore claim 1 is rejected as indefinite.
Claim 1 recites “aldosterone antagonist” which renders the claim scope indefinite. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, “aldosterone antagonist” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims. Although it is reasonably understood that the phrase encompasses at least spironolactone, eplerenone, canrenone, potassium canrenoate, finerenone, prorenone, progesterone, drospirenone, gestodene, and benidipine (see, e.g.., Spec. filed 2/16/2024 at 18 at line 29 to page 20 at line 13), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.). Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not qualify as an “aldosterone antagonist” at instant claim 1, an artisan would be unable to identify infringing from non-infringing compounds, commensurate in scope with the instant claim, and therefore claim 1 is rejected as indefinite.
Claim 1 recites “Insulin modulator” which renders the claim scope indefinite. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, “insulin modulator” does not correspond to an unambiguous structure/function relationship of record, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims. Although it is reasonably understood that the phrase encompasses at least exenatide and the expressly identified compounds (see, e.g.., Spec. filed 2/16/2024 at 15 at line 13 to page 16 at lines 5), it is unclear if the term encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.). Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not qualify as an “insulin modulator” at instant claim 1, an artisan would be unable to identify infringing from non-infringing compounds, commensurate in scope with the instant claim, and therefore claim 1 is rejected as indefinite.
Claims 4, 6, 11, and 15 use the phrase “structural or functional analogue” with reference to potassium canrenoate and exenatide, which renders the pending claim scope indefinite. The Specification identifies that this phrase does not meaningfully correspond to any specific or particular structure or function:
As used herein, a structural analogue, also known as a chemical analogue, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analogue can be imagined to be formed, at least theoretically, from the other compound.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 1-6).
As used herein, functional analogues are chemical compounds that have similar physical, chemical, biochemical, or pharmacological properties to that of another compound. Functional analogues are not necessarily structural analogues with a similar chemical structure.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 5-10).
Accordingly, the metes and bounds of such phrases and the associated definitions depend upon the arbitrary interpretation of at least what does or does not constitute “similar” to the inventor or an artisan (see also Spec. filed 2/16/2024 at 17 at lines 14-20) (see, e.g., MPEP § 2173.05(b)(II)-(III), noting that “similar” has been previously deemed indefinite by the courts). Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, “structural or functional analogue” does not correspond to any unambiguous structure/function relationship of record with respect to any particular structure, but instead appears to be an attempt to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unspecified structures to achieve, rather than identifying what structures actually achieve the desired function, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claims. Although it is reasonably understood that the phrase encompasses specifically enumerated compounds expressly identified as analogues of exenatide or potassium canrenoate, it is unclear if the phrase encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.). This issue is further complicated because a “functional analogue” does not need to share a particular function in common, but instead can share any arbitrarily “similar physical, chemical, biochemical, or pharmacological properties to that of another compound” (see, e.g., Spec. filed 2/16/2024 at 6 at lines 5-10), which could vary from receptor binding, overall charge, molecular weight, etc. (see, e.g., MPEP § 2173.05(b), noting that reference to an object that is variable may render a claim indefinite, and here the metric for identifying a “functional analogue” may vary from physical, chemical, biochemical, or pharmacological properties without limit). Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not qualify as an “structural or functional analogue” at instant claims 4, 6, 11, and 15, an artisan would be unable to identify infringing from non-infringing compounds, commensurate in scope with the instant claim, and therefore claims 4, 6, 11, and 15 are rejected as indefinite.
Claims 34-37 each recite an active method step (“the combination is formulated for….”), which render the claims indefinite. Per MPEP § 2173.05(p)(II), a single claim reciting a product and a method step utilizing that product is indefinite because it is unclear if infringement occurs before, during, or after the completion of the claimed step. Accordingly, claims 34-37 are rejected as indefinite. For purposes of applying prior art, these claims are interpreted as reciting “the combination is capable of being formulated for”, which is reasonable and would constitute a recitation of intended or expected use.
Claims 2-6, 11, 15, 18, and 34-37 each depend directly or indirectly from an indefinite claim, but fail to clarify the indefiniteness of one or more claims upon which they depend. Accordingly, these claims are rejected as indefinite for reasons applied to the claim upon which they depend.
Claims 1-6, 11, 15, 18, and 34-37 are rejected.
Claim Rejections - 35 USC § 112(a), Written Description
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 1-6, 11, 15, 18, 34-37, and 72 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.
Brief Statement of the Issue(s)
The claims rely upon functional limitations to describe a genus of unknown compounds (e.g., “Nurr1 agonist”, “aldosterone antagonist”, “Insulin modulator”, “structural or functional analogue”), but such terms do not correspond to a clear structure/function relationship permitting artisans to reasonably identify what possible structures do or do not fall within the scope of the instant claims.
Claim Scope
Claim 1 is representative of the pending claims scope and recites a “combination” of at least two components (see, e.g., instant claim 1), wherein one or more components are defined at least in part using functional limitations or functional terminology.
The applicable claim interpretations have been set forth above under 35 USC §112(b) and in a separate claim interpretation section. Those discussions are incorporated herein. The claims rely upon functional limitations to describe a genus of unknown compounds (e.g., “Nurr1 agonist”, “aldosterone antagonist”, “Insulin modulator”, “structural or functional analogue”), but such terms do not correspond to a clear structure/function relationship permitting artisans to reasonably identify what possible structures do or do not fall within the scope of the instant claims. For example, it is unclear if such functionally defined genera encompass less than ten, a few dozen, or a few trillion different compounds having substantially different structures (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.).
Accordingly, the claim scope appears to be vast and highly varied.
It is unclear if the claim scope encompass trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
Actual Reduction to Practice
The originally filed disclosures tests and reduces to practice highly similar combinations of intravenous formulations including either 20 mg/kg or 0.5 mg/kg amodiaquine, as well as one or more of: 0.05µg/kg exenatide, 0.33 mg/kg Potassium canrenoate, and 1 µg/kg Glibenclamide (see, e.g., Spec. filed 2/16/2024 at Table 1 on 86 at Group #3M and 4M; see id. at Table 3B on 95 at Group #6M, 9M, 10M, and 11M; see id. at Table “Study Design” on 101 at Group # 3M, 4M, and 5M).
Accordingly, highly limited species were disclosed on record, in combination for simultaneous administration via intravenous injection, comprising a combination of either 20 mg/kg or 0.5 mg/kg amodiaquine, and one or more of exenatide, potassium canrenoate, and glibenclamide.
Zero examples of a Nurr1 agonist other than amodiaquine were reduced to practice.
Zero examples of an aldosterone antagonist other than potassium canrenoate were reduced to practice.
Zero examples of an insulin modulator other than exenatide were reduced to practice.
Zero examples of a sulfonylurea other than glibenclamide were reduced to practice.
Zero examples of any functional “structural or functional analogues” were tested and reduced to practice.
Zero examples of a Nurr1 agonist, an aldosterone antagonist, or an insulin modulator having the structure of aptameric nucleic acid, locked nucleic acid, peptide nucleic acid, Gapmer, enzyme, antibody, microRNA, or siRNA were reduced to practice or even identified on record.
Zero examples of a “combination” being made and used sequentially or non-simultaneously were reduced to practice.
Accordingly, the claims are directed to a vast and highly varied genus of trillions of potential species, but the instant disclosure only reduces to practice about 10 highly similar species of “combination” as presently claimed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass an essentially infinite number of “combinations” of functionally defined components (e.g., a “Nurr1 agonist”, “aldosterone antagonist”, “Insulin modulator”), but reduce to practice examples using only one “Nurr1 agonist”, one “aldosterone antagonist”, one “insulin modulator”, and only reduce to practice “combinations” wherein such components are administered simultaneously; but zero guidance regarding a “Nurr1 agonist”, “aldosterone antagonist”, or “Insulin modulator” having the structure of aptameric nucleic acid, locked nucleic acid, peptide nucleic acid, Gapmer, enzyme, antibody, microRNA, or siRNA were reduced to practice or even identified on record.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero examples of structural variability of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Here, the terms “Nurr1 agonist”, “aldosterone antagonist”, “Insulin modulator” are understood to reasonably read upon and encompass at least the exact compounds identified for each in the specification (see, e.g.., Spec. filed 2/16/2024 at 8 at lines 1-15; id. at 18 at line 29 to page 20 at line 13; id. at 15 at line 13 to page 16 at lines 5), these exact compounds are not actually identified in the pending claims, and the pending claims are therefore not currently limited to such species that are adequately described in the original disclosure. Rather, “Nurr1 agonist”, “aldosterone antagonist”, and “Insulin modulator” do not correspond to any unambiguous structure/function relationship of record, but instead these generic terms appear to be an attempt by the Applicant to describe a genus of unknown metes and bounds by reciting a function Applicant hopes and desires for unknown structures to achieve, rather than identifying what structures actually achieve the desired function. This is problematic, because as presently claimed, the claim scope is not limited to exemplified embodiments, but broadly encompasses all possible members of such genera, including ones not described and those not yet discovered, including for example aptameric nucleic acids, locked nucleic acids, peptide nucleic acids, Gapmers, enzymes, antibodies, microRNAs, siRNAs, tetrapeptides, decapeptides, etc., etc., without limitation.
Regarding the phrase “structural or functional analogue”, the Specification appears to admit that this phrase does not meaningfully correspond to any specific or particular structures or functions:
As used herein, a structural analogue, also known as a chemical analogue, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analogue can be imagined to be formed, at least theoretically, from the other compound.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 1-6).
As used herein, functional analogues are chemical compounds that have similar physical, chemical, biochemical, or pharmacological properties to that of another compound. Functional analogues are not necessarily structural analogues with a similar chemical structure.
(see, e.g., Spec. filed 2/16/2024 at 6 at lines 5-10).
It is unclear what does or does not constitute a “similar” structure or property. Accordingly, the metes and bounds of such phrases and the associated definitions appear to describe, abstractly and generically, a genus of unknown size and of unknown structures, that exhibit functionality that the Applicant hopes and desires to achieve, but without actually providing descriptions of the structures that actually achieve such functionality. Although it is reasonably understood that the phrase encompasses specifically enumerated compounds expressly identified as analogues of exenatide or potassium canrenoate, it is unclear if the phrase encompasses a vast number of unknown, but highly varied compounds (e.g., peptides, enzymes, microRNAs, siRNAs, aptamers, small molecules, LNAs, PNAs, Gapmers, etc.). This issue is further complicated because a “functional analogue” does not need to share a particular function in common with another “functional analogue”, but instead can share any arbitrarily “similar physical, chemical, biochemical, or pharmacological properties to that of another compound” (see, e.g., Spec. filed 2/16/2024 at 6 at lines 5-10), which could vary from a particular Kd for receptor binding, an overall charge at a particular but undisclosed pH, a molecular weight range, etc., etc. Accordingly, a “functional analogue” as described need not share any particular common property with other “functional analogues”, but instead may by physical, chemical, biochemical, and/or pharmacological properties from other members of the same genus. This means that “structural or functional analogue” is utilized in the claims to create a genus of chemical structures having unrelated members that do not necessarily have to share any common structure or function with one another.
Accordingly, the functional limitations and descriptions in the pending claims are only utilized as a vague attempt to capture unknown and undisclosed structures, sufficient to achieve some functional result that Applicant hopes and desires that the disclosed invention is able to achieve. However, the disclosure but does not meaningfully disclose an unambiguous structure/function relationship permitting an artisan to identify, a priori, which exact structures do or do not satisfy the functional limitations at issue.
Accordingly, basic identifying characteristics pertinent to the claimed genus are left unanswered, including “what prior art compounds constitute a ‘Nurr1 agonist’, ‘insulin modulator’, ‘aldosterone antagonist’, or otherwise constitute a ‘structural or functional analogue’ of exenatide or potassium canrenoate?” The inability to address this basic question regarding claim scope supports a determination of lack of written description because
the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not qualify as a “Nurr1 agonist”, “insulin modulator”, “aldosterone antagonist”, or otherwise constitute a “structural or functional analogue” of exenatide or potassium canrenoate, an artisan would be unable to identify infringing from non-infringing compounds, commensurate in scope with the instant claims. Therefore, applicant “cannot lay claim to the subject matter”.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems, biochemistry, and molecular biophysics of chemical structures. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly what compounds would be capable of acting as a “Nurr1 agonist”, “insulin modulator”, “aldosterone antagonist”, or otherwise constitute a “structural or functional analogue” of exenatide or potassium canrenoate commensurate in scope with the instant claims.
Accordingly, in the absence of sufficient structure/function teachings identifying particular compounds capable of acting as a “Nurr1 agonist”, “insulin modulator”, “aldosterone antagonist”, or otherwise constitute a “structural or functional analogue” of exenatide or potassium canrenoate commensurate in scope with the pending claims, as required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that it is prima facie unclear what structures are infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claims 1-6, 11, 15, 18, 34-37, and 72 are rejected
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.
[Prior Art Rejection 01]
Claim(s) 1-2, 15, 18, and 34-37 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US 2019/0175583 Al.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section and in preceding rejections. Those interpretations and discussions are incorporated into the instant rejection.
Regarding instant claims 1-2, 15, 18, and 34-37, US’583 teaches and discloses methods utilizing pharmaceutical compositions comprising the combination of amodiaquine and exenatide, wherein the pharmaceutical compositions would be readily inferred to comprise a pharmaceutically acceptable carrier, diluent or excipient (see, e.g., US’583 at title, claims 1 and 4-5; see also US’583 at Table 5 at ¶[0192], disclosing preparation of amodiaquine and exenatide). Regarding instant claims 34-37, these claims have been rejected as indefinite for reasons set forth above. For purposes of the instant rejection, the disclosed and claimed formulations (see, e.g., US’583 at title, claims 1 and 4-5; see also US’583 at Table 5 at ¶[0192], disclosing preparation of amodiaquine and exenatide) are readily understood to satisfy the requirements of claims 34-37 because the prior art explicitly teaches that such pharmaceutical compositions of the present invention may be administered via oral, intranasal, intravenous, and subcutaneous routes (see, e.g., US’583 at ¶[0074]). Accordingly, an artisan would readily and at once envisage that the disclosed compositions were capable of being formulated in the manner claimed.
Accordingly, claims 1-2, 15, 18, and 34-37 are rejected.
[Prior Art Rejection 02]
Claim(s) 1-2, 15, 18, and 34-37 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US 10,792,280.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section and in preceding rejections. Those interpretations and discussions are incorporated into the instant rejection.
Regarding instant claims 1-2, 15, 18, and 34-37, US’280 teaches and discloses methods utilizing pharmaceutical compositions comprising the combination of amodiaquine and exenatide, wherein the pharmaceutical compositions would be readily inferred to comprise a pharmaceutically acceptable carrier, diluent or excipient (see, e.g., US’280 at claims 1, 3-4, and 8; see also US’280 at col. 29 at line 30 to col. 30 at line 10, disclosing preparation of amodiaquine and exenatide). Regarding instant claims 34-37, these claims have been rejected as indefinite for reasons set forth above. For purposes of the instant rejection, the disclosed and claimed formulations (see, e.g., US’280 at claims 1, 3-4, and 8; see also US’280 at col. 29 at line 30 to col. 30 at line 10) are readily understood to satisfy the requirements of claims 34-37 because the prior art explicitly teaches that such pharmaceutical compositions of the present invention may be administered via oral, intranasal, intravenous, and subcutaneous routes (see, e.g., US’280 at col. 10 at lines 25-40). Accordingly, an artisan would readily and at once envisage that the disclosed compositions were capable of being formulated in the manner claimed.
Accordingly, claims 1-2, 15, 18, and 34-37 are rejected.
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.
[Prior Art Rejection 03]
Claims 1-2, 15, 18, and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0175583 Al as applied to claims 1-2, 15, 18, and 34-37 above.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section and in preceding rejections. Those interpretations and discussions are incorporated into the instant rejection. The instant rejection pertains to a non-elected species comprising a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide
The teachings of the primary reference as applied to claims 1-2, 15, 18, and 34-37 has been discussed above, and those teachings are incorporated herein.
The primary reference differs from a non-elected species within the scope of instant claims 1-2, 15, 18, and 34-37 as follows: Although the primary reference reduces to practice a species comprising amodiaquine and exenatide in a pharmaceutical composition, the primary reference does not explicitly reduce to practice an embodiment comprising amodiaquine, exenatide, and further comprising a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide. Therefore, the relevant issue is whether or not such a combination would be obvious in view of the prior art.
Although not reduced to practice, the primary reference explicitly teaches, claims, and directs artisans to utilize pharmaceutical formulations comprising amodiaquine, exenatide, and also further comprising an “insulin secretagogue”, which may be a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide (see, e.g., US’583 at claim 1, ¶¶[0019], [0058], [0063], note that “glibenclamide” is misspelled at claim 1 as glybenclamide).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination of prior art elements (i.e., amodiaquine, exenatide, and a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide) according to known methods of making pharmaceutical formulations suitable for use in methods of treating diabetes as recited and claimed by the primary reference, wherein such combination yields predictable results, namely a pharmaceutical composition comprising known prior art elements suitable for use in known prior art methods, wherein such pharmaceutical compositions would be predictably usable in the prior art methods, exactly as claimed and disclosed by the primary reference (see, e.g., MPEP § 2143(I)(A), (F), (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the prior art to combine known chemical compounds according to known methods to obtain a pharmaceutical compositions suitable for use in prior art methods, exactly as taught and disclosed by the prior art.
Claims 1-2, 15, 18, and 34-37 are rejected.
[Prior Art Rejection 04]
Claims 1-2, 15, 18, and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,792,280 as applied to claims 1-2, 15, 18, and 34-37 above.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section and in preceding rejections. Those interpretations and discussions are incorporated into the instant rejection. The instant rejection pertains to a non-elected species comprising a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide
The teachings of the primary reference as applied to claims 1-2, 15, 18, and 34-37 has been discussed above, and those teachings are incorporated herein.
The primary reference differs from a non-elected species within the scope of instant claims 1-2, 15, 18, and 34-37 as follows: Although the primary reference reduces to practice a species comprising amodiaquine and exenatide in a pharmaceutical composition, the primary reference does not explicitly reduce to practice an embodiment comprising amodiaquine, exenatide, and further comprising a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide. Therefore, the relevant issue is whether or not such a combination would be obvious in view of the prior art.
Although not reduced to practice, the primary reference explicitly teaches, claims, and directs artisans to utilize pharmaceutical formulations comprising amodiaquine, exenatide, and also further comprising an “insulin secretagogue”, which may be a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide (see, e.g., US’280 at claims 1, 3-4, and 8, col. 3 at lines 35-45, col. 7 at lines 55-60, note that “glibenclamide” is misspelled at claim 1 as glybenclamide).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination of prior art elements (i.e., amodiaquine, exenatide, and a sulfonylurea such as glibenclamide, glimepiride, glipizide or gliclazide) according to known methods of making pharmaceutical formulations suitable for use in methods of treating diabetes as recited and claimed by the primary reference, wherein such combination yields predictable results, namely a pharmaceutical composition comprising known prior art elements suitable for use in known prior art methods, wherein such pharmaceutical compositions would be predictably usable in the prior art methods, exactly as claimed and disclosed by the primary reference (see, e.g., MPEP § 2143(I)(A), (F), (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the prior art to combine known chemical compounds according to known methods to obtain a pharmaceutical compositions suitable for use in prior art methods, exactly as taught and disclosed by the prior art.
Claims 1-2, 15, 18, and 34-37 are rejected.
[Prior Art Rejection 05]
Claims 1-6, 11, 15, 18, 34-37, and 72 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0333519 B2 (Nov. 23, 2017) in view of Kinoshita et al.1 and Maier et al.2.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section and in preceding rejections. Those interpretations and discussions are incorporated into the instant rejection.
US’519 teaches, discloses, and claims pharmaceutical compositions for use in the treatment of at least reperfusion injury of the brain (see, e.g., US’519 at claim 34, 38-43, 66-68, and 71) and stroke (see, e.g., US’519 at ¶[0234]) . Regarding instant claims 1, 3-6, 11, 15, 18, 34-37, 72, and a pharmaceutical composition comprising the aldosterone antagonist of potassium canrenoate and the insulin modulator of exenatide, US’519 teaches, discloses, and claims pharmaceutical compositions comprising the insulin modulator of exenatide in combination with the aldosterone antagonist of potassium canrenoate (see, e.g., US’519 at claims 1, 13-14, 16, 62-70); wherein exenatide is present at “about 0. 005 to about 0.15µg/kg” (see, e.g., US’519 at ¶[0277]); wherein potassium canrenoate is present at “about 1 to about 10 mg/kg” (see, e.g., US’519 at ¶[0278]); wherein such pharmaceutical compositions are taught and disclosed for use in the treatment of at least reperfusion injury of the brain (see, e.g., US’519 at claim 34, 38-43, 66-68, and 71). Regarding claims 34-37 and formulations for various administration routes, these claims have been rejected as indefinite for reasons set forth above. For purposes of the instant rejection, the disclosed and claimed formulations of US’519 are readily understood to satisfy the requirements of claims 34-37 because the pharmaceutical formulations are explicitly identified as capable of being suitable for parenteral (intravenous, subcutaneous), oral, and any inhalation/transmucosal administration routes (i.e., an artisan would readily infer that inhalation/transmucosal administration routes included intranasal administration routes) (see, e.g., US’519 at ¶[0161]). Accordingly, an artisan would readily and at once envisage or otherwise reasonably infer that the disclosed compositions were capable of being formulated in the manner claimed. Regarding instant claims 1-6, 11, 15, 18, 34-37, 72, and a pharmaceutically acceptable diluent, excipient, or carrier, US’519 teaches that the compositions may comprise any carriers or diluents known in the pharmaceutical arts, suitable for use in formulations for parenteral (intravenous, subcutaneous), oral, and any inhalation/transmucosal administration (see, e.g., US’519 at ¶¶[0158]-[0162]).
The primary reference differs from the instant claims as follows: Although US’519 discloses pharmaceutical compositions for use in the treatment of reperfusion injuries of the brain comprising exenatide and potassium canrenoate, US’519 does not explicitly teaches that such compositions may further comprise a Nurr1 agonist, such as amodiaquine. Therefore, the relevant issue is whether or not it would be obvious to modify pharmaceutical compositions and combinations, for use in the treatment of reperfusion injuries of the brain, by combining them with amodiaquine.
Nurr1 was an art-recognized target for neurological disorders initiated by rupture of blood vessels and leakage of blood constituents into the brain: Kinoshita pertains to brain injuries, and in particular intracerebral hemorrhage (ICH), which is a neurological disorder initiated by rupture of blood vessels and leakage of blood constituents into the brain (see, e.g., Kinoshita at title, abs, 48 at col I-II at § 1. Introduction). Kinoshita identifies that the Nurr1 was thought to be “a regulator of inflammatory responses in the brain” that potentially “regulated[d] neuronal viability” (see, e.g., Kinoshita at 48 at col I-II at § 1. Introduction), and identifies that a Nurr1 agonist was previously shown to protect neurons in a mouse model of Parkinson’s disease (see id.).
Amodiaquine was a prior art element and art-recognized Nurr1 agonist: Kinoshita teaches that amodiaquine is a prior art element and art-recognized Nurr1 agonist (see, e.g., Kinoshita at title, abs), and further identifies that amodiaquine was utilized to treat a mouse model of intracerebral hemorrhage (ICH) (see id).
Amodiaquine treatment led to desirable outcomes in animal models of brain injury: Kinoshita discloses that treatment with amodiaquine desirably diminished perihematomal activation of microglia/macrophages and astrocytes, as well as suppress ICH-induced mRNA expression of inflammatory mediators (i.e., IL-1β, CCL2 and CXCL2), which lead to amelioration of motor dysfunction caused by ICH (see, e.g., Kinoshita at title, abs, 51 at §§ 3.3-3.5, page 52 at § 3.6), and that “amodiaquine markedly improved the recovery of motor functions of mice after ICH” (see, e.g., Kinoshita at 53 at Col II at last ¶).
The predicted and expected dosages suitable for amodiaquine treatment were known in the art: Kinoshita identifies that the usage of amodiaquine to alleviate brain injury and inflammatory responses should be further studied (see, e.g., Kinoshita at 54 at col I at 1st full ¶), and explicitly directs artisans to utilize amodiaquine at 5-15 mg/kg, 20 mg/kg, or 40 mg/kg to avoid known toxicity issues (see, e.g., Kinoshita at 53 at col I-II at bridging ¶). Therefore, an artisan would readily appreciate that amodiaquine would be expected to show benefits without toxicity at least at the range of 5-40 mg/kg (see id.).
An artisan would readily appreciate that the observations of Kinoshita could be reasonably and predictably extended to other brain injuries: In view of Kinoshita, an artisan would readily expect and predict that Nurr1 targeting therapeutics could be utilized to treat ischemic stroke and intracerebral hemorrhages (i.e., hemorrhagic stroke or brain bleed) (see, e.g., Kinoshita at 52-53 at bridging ¶, noting that “Nurr1 expression in specific brain regions was upregulated under several pathological conditions including … ischemic stroke”) and that the “focus of the present study” was more generalizable to the question of “whether amodiaquine could alleviate brain injury and inflammatory responses” (see, e.g., Kinoshita at 54 at col I at 1st full ¶). Kinoshita also identifies that benefits of such treatment had been reported in a mouse model of Parkinson’s disease (see, e.g., Kinoshita at 48 at col I-II at § 1. Introduction). Accordingly, the expected and observed benefits of suppressing mRNA expression of inflammatory mediators (i.e., IL-1β, CCL2 and CXCL2) and diminishing perihematomal activation of microglia/macrophages and astrocytes (see, e.g., Kinoshita at title, abs, 51 at §§ 3.3-3.5, page 52 at § 3.6) would be reasonably expected to occur in other brain injuries.
Treatment of ICH and neurological disorders initiated by rupture of blood vessels and leakage of blood constituents into the brain3 as taught by Kinoshita would be readily understood by artisans to be within the scope of US’519: US’519 teaches, discloses, and claims pharmaceutical compositions for use in the treatment of at least reperfusion injury of the brain (see, e.g., US’519 at claim 34, 38-43, 66-68, and 71) and stroke (see, e.g., US’519 at ¶[0234]). Therefore ICH, which is a type of brain bleed and type of hemorrhagic stroke is within the scope of treatments taught and disclosed by US’519 under two rationales:
First, ICH as taught by Kinoshita is understood to be a type of “stroke” as encompassed by US’519, namely a hemorrhagic stroke, and US’519 explicitly teaches:
[0234] In one embodiment, the claimed combinations are for administration to a subject with stroke. Stroke is when poor blood flow to the brain results in cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding.…Ischemic stroke treatment includes surgery to open up (reperfusion) the arteries to the brain in those with problematic narrowing.
(see, e.g., US’519 at ¶[0234]).
Accordingly, an artisan would readily appreciate that both Kinoshita and US’519 pertain to treatments for types of hemorrhagic strokes.
Second, US’519 covers any type of “reperfusion injury”:
[0200] As used herein, the term "reperfusion injury" refers to the damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation, mitochondrial dysfunction and oxidative damage through the induction of oxidative stress rather than restoration of normal function. Reperfusion injury can occur after a spontaneously occurring event, e.g., arterial blockage, or a planned event, e.g., any of a number of surgical interventions.
(see, e.g., US’519 at ¶[0200]).
This is pertinent because an intracerebral hemorrhage (ICH) is a neurological disorder initiated by rupture of blood vessels and leakage of blood constituents into the brain (see, e.g., Kinoshita at title, abs, 48 at col I-II at § 1. Introduction), and Maier identifies that blood-brain barrier injuries and brain hemorrhages are an art-recognized type of reperfusion injury that may occur after an ischemic stroke (see, e.g., Maier at title, abs, 929 at col I-II at bridging ¶, referring to “Hemorrhages after reperfusion”).
Accordingly, the teachings of US’519 and Kinoshita are related because both documents pertain to the treatment of hemorrhagic strokes, and an artisan would readily appreciate that ICH (or any neurological disorder initiated by rupture of blood vessels and leakage of blood constituents into the brain) may be a “reperfusion injury” (see, e.g., US’519 at ¶[0200]; see, e.g., Maier at title, abs, 929 at col I-II at bridging ¶, referring to “Hemorrhages after reperfusion”).
In summary, US’519 teaches pharmaceutical compositions comprising exenatide and potassium canrenoate for use in treating strokes and reperfusion injuries, which differs from the instant claim scope only by the absence of the Nurr1 agonist amodiaquine. However, amodiaquine is a prior art element, which was taught and disclosed for use in the treatment of a type of hemorrhagic stroke and reperfusion injury, namely ICH (i.e., neurological disorder initiated by rupture of blood vessels and leakage of blood constituents into the brain), wherein administration of amodiaquine would be predicted and expected to alleviate a brain injury specifically by (i) diminishing perihematomal activation of microglia/macrophages and astrocytes; (ii) as well as suppress ICH-induced mRNA expression of inflammatory mediators (i.e., IL-1β, CCL2 and CXCL2), would be expected to lead to amelioration of motor dysfunction caused by ICH (see, e.g., Kinoshita at title, abs, 51 at §§ 3.3-3.5, page 52 at § 3.6).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the claimed invention is the combination of prior art elements (i.e., amodiaquine, exenatide, and potassium canrenoate) according to known methods of treating ICH (e.g., a reperfusion injury and type of hemorrhagic stroke) as taught and suggested by US’519 and Kinoshita, wherein the combination would predictably treat ICH as taught and suggested by US’519, and wherein amodiaquine would predictably diminish perihematomal activation of microglia/macrophages and astrocytes, suppress ICH-induced mRNA expression of inflammatory mediators (i.e., IL-1β, CCL2 and CXCL2), and lead to amelioration of motor dysfunction caused by ICH (see, e.g., MPEP § 2143(I)(A), (G)). Furthermore, each prior art component would merely perform its art-recognized function in combination as it does alone.
Second, or alternatively, the claimed invention is the obvious combination of two compositions (i.e., the exenatide and potassium canrenoate composition of US’519, and the composition comprising amodiaquine as taught by Kinoshita) taught to be useful for the same purpose (i.e., treating reperfusion injuries and strokes, including hemorrhagic strokes such as ICH), in order to form a third “combined” composition to be used for the very same purpose of treating reperfusion injuries and strokes, including hemorrhagic strokes such as ICH; per MPEP § 2144.06(I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art" (see, e.g., In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)).
Third, the claimed invention is the simple substitution of one anti-inflammatory agent into the disclosed compositions of exenatide and potassium canrenoate composition of US’5194, wherein the substituted anti-inflammatory agent is amodiaquine as disclosed by Kinoshita, wherein substituted amodiaquine would yield predictably results, namely the amodiaquine would predictably suppress ICH-induced mRNA expression of inflammatory mediators (i.e., IL-1β, CCL2 and CXCL2) upon administration to patient in need of treatment of reperfusion injuries and strokes, including hemorrhagic strokes such as ICH, exactly as taught and suggested by the prior art (see, e.g., MPEP § 2143(I)(B), (G), MPEP § 2144.07).
Accordingly, the claimed invention, comprising a combination of three prior art element taught and disclosed for use in the same or overlapping patient populations, is obvious.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the prior art to combine known chemical compounds according to known methods to obtain a pharmaceutical compositions suitable for use in prior art methods, exactly as taught and disclosed by the prior art.
Claims 1-6, 11, 15, 18, 34-37, and 72 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO2021005147A1 (Jan. 14, 2021; cited in IDS filed 2/19/2024 at cite No. 1) pertains to combinations of a sulfonylurea and at least one of an insulin modulator (e.g., exenatide) and an aldosterone antagonist (e.g., potassium canrenoate) for use in treatment of stroke, neurodegenerative disorders, ischemia, and reperfusion injuries (see, e.g., WO’147 at title, abs, claims).
US10172914B2 corresponds to US 2017/0333519 B2, which has been applied and discussed above.
US 20090005297 A1 identifies that an ischemia reperfusion injury is art-recognized as including any type of stroke, intracerebral hemorrhage, or myocardial Infarction (see, e.g., US’297 at ¶¶[0006], [0109]).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Kinoshita et al., A Nurr1 agonist amodiaquine attenuates inflammatory events and neurological deficits in a mouse model of intracerebral hemorrhage. J Neuroimmunol. 2019 May 15;330:48-54. doi: 10.1016/j.jneuroim.2019.02.010. Epub 2019 Feb 22. PMID: 30825859.
2 Maier et al., Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Ann Neurol. 2006 Jun;59(6):929-38. doi: 10.1002/ana.20850. PMID: 16673393.
3 See, e.g., Kinoshita at title, abs, 48 at col I-II at § 1. Introduction.
4 See US’519 at claims 1 and 12.
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