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 .
DETAILED ACTION
The preliminary amendment dated 13 May 2024, in which claims 4, 5, 9-12, 14, 16, 19, 22-24, 28, 31 have been amended, and claims 2-3, 6-8, 17-18, 20-21, 29-30, 32-42 have been cancelled, is acknowledged.
Claims 1, 4-5, 9-16, 19, 22-28 and 31 are pending in the instant application.
Claims 4, 5 are withdrawn, as being drawn to a non-elected species.
Claims 1, 9-16, 19, 22-28 and 31 are being examined.
Priority
The instant application is a National Stage entry of International Application No. PCT/US2022/071775, filed on 18 April 2022, which claims priority from U.S. Provisional Patent Application No. 63/176,749, filed on 19 April 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 29 January 2025 and 12 February 2025 are acknowledged and considered.
Election/Restrictions
Applicants’ election without traverse of multiple sclerosis as the disorder to be treated,
for initial examination, in the Reply of 27 March 2026, is acknowledged.
Since the election was made without traverse, the requirement for restriction/election is herein maintained and is made FINAL.
Claims 1, 9-16, 19, 22-28 and 31 have been examined to the extent they read on the elected species, and the following objections and rejections are made below.
Claim objection
Claim 1 is objected to because the recitation (on line 1) “in a subject” could read –in a subject in need thereof--.
Claims 25-27 are objected to because the recitation “wherein the subject is administered the composition in at least two doses per day” is unnecessary. That is because claim 25 depends on claim 24 (and claim 26 depends on claim 25, and claim 27 depends on claim 26), and claim 24 already recites that the subject is administered the composition in at least two doses per day.
Claim 1 is objected to because the recitation “atopic dermatitis and psoriasis,” (which is part of a list) should read –atopic dermatitis, psoriasis, --.
Claim 14 is objected to because the recitation “the subject comprises a human subject” should read –the subject is a human subject--.
Claim 31 is objected to because the recitation “the composition comprises a solution or a tablet” could read --the composition is in the form of a solution or tablet--.
Claim 28 is objected to because it is drawn to the method of claim 24, wherein the two doses are administered at a time period of at least 10 hours apart; yet, claim 24 recites that the subject is administered the composition in at least two doses per day. The examiner understands the claim and suggests that claim 28 be amended to recite that the subject is administered the composition in two doses per day administered at a time period of at least 10 hours apart.
Objection to the Drawings
The drawings submitted on 10/18/2023 are objected to because Fig. 5A-D is not clear; some of the text is unintelligible. Appropriate correction is required.
Claim Rejections- 35 USC 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 9-16, 19, 22-28 and 31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation neuroinflammatory conditions, and the claim also recites multiple sclerosis, Alzheimer’s disease, which are the narrower statements 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 19, 22, 24-28 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 12 is drawn to the method of claim 1, wherein the method comprises administering a daily dose of the composition to the subject.
Claim 19 is drawn to the method of claim 12, wherein the composition comprises 20- 150 mg/kg of the compound in the daily dose. The claim is unclear because it is unclear how a composition comprises a dose. A composition comprises an amount of a compound expressed in mg or grams; a dose refers to a method of administering/treating and is expressed in mg/kg or g/kg.
The same applies to claim 22.
In the interest of compact prosecution, claim 19 is interpreted to be drawn to the method of claim 12, wherein the daily dose comprises 20- 150 mg/kg compound.
Further, claim 24 is drawn to the method of claim 12, wherein the subject is administered the composition in at least two doses per day; yet claim 12 recites administering a (one) daily dose of the composition to the subject. As such, there is insufficient antecedent basis for the recitation “at least two doses per day” of claim 24, in claim 12.
Appropriate correction is required.
Claim 11 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.
Claim 11 is indefinite because it recites that the compound demonstrates significant biodistribution to the plasma, liver, mesenteric lymph nodes, brain, spinal cord, lung, and spleen over a control, wherein the control comprises sodium butyrate. It is unclear how a compound can “demonstrate” biodistribution in a method of treatment. The examiner acknowledges the teachings in the Specification [0028] FIG. 4A-G shows the Biodistribution of sodium butyrate, serine butyrate and threonine butyrate after oral administration. The amount of butyrate quantified in the plasma (A), liver (B), mesenteric lymph nodes (mLNs) (C), brain (D), spinal cord (E), spleen (F), and lung (G). Blood was collected by cheek bleeding at 0.5 hr and 3 hr post oral gavage. Mice were sacrificed at 3 hr and 6 hr post oral gavage, and organs were collected for butyrate quantification. Spleens were collected only at 3 hr post-administration.
Based on these teachings, the distribution of compound to plasma and to organs inherently occurs upon administration of the compound, yet the claim does not recite a relationship between the administration of compound and the amount of compound found in different organs. It is unclear what is meant by a compound “demonstrating” biodistribution.
Further, the term “significant” renders the claim indefinite, because the Specification does not define the term “significant”, and “significant” is a relative term- what is significant in one context may not be significant in another context. Furthermore, claim 11 seems to compare biodistribution to plasma and to different organs achieved with a compound of claim 1 over a control, where the control comprises sodium butyrate. Yet, claim 1, as written, does not recite sodium butyrate, nor does it recite a control; claim 11 does not explain how the biodistribution is achieved, and whether said biodistribution is the result of administering a compound. If that were the case, it is unclear how a method of treating, for example, multiple sclerosis with a compound of claim 1 would include administering sodium butyrate.
Appropriate clarification is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9-16, 19, 22-28 and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification while being enabling for the treatment of multiple sclerosis in a subject with serine butyrate, threonine butyrate or tyrosine butyrate, does not reasonably provide enablement for the treatment of the claimed scope of disorders selected from inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis and psoriasis, pulmonary fibrosis, and systemic sclerosis with serine butyrate, threonine butyrate or tyrosine butyrate. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir.1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breath of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
Claims 1, 9-16, 19, 22-28 and 31 are drawn to a method of treating a disorder selected from inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis, psoriasis, pulmonary fibrosis, and systemic sclerosis in a subject with an oral composition comprising serine butyrate, threonine butyrate or tyrosine butyrate. Thus, claims 1, 9-16, 19, 22-28 and 31, taken together with the specification, imply that serine butyrate, threonine butyrate or tyrosine butyrate can treat any disorder selected from the group of inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis, psoriasis, pulmonary fibrosis, and systemic sclerosis.
The claims are broader than the disclosure.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
In terms of the scope of the diseases covered, conditions selected from the group of inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis, psoriasis, pulmonary fibrosis, and systemic sclerosis
are extremely diverse, and fall into an assortment of categories.
Rahman et al. (J Rheumatol. 2010, 85, 11-26, cited in PTO-892) teach that immune-mediated inflammatory disease (IMID) is a concept used to describe a group of chronic and potentially disabling conditions that share common inflammatory pathways. Rahman teaches that both genetic and environmental factors play important roles in the development of these diseases (page 11, left column).
In terms of genetic factors, Rahman teaches (page 12, left column, last paragraph, Table 1) that the HLA genetic region is linked to immune disorders, some IMID such as rheumatoid arthritis or psoriasis being strongly associated to HLA. Rahman teaches that the HLA region contributes to one-third of the genetic risk for developing rheumatoid arthritis (page 13, right column).
Mechanistically, Rahman teaches (page 14, left column, under T cell differentiation) that Th17 cells have a significant role in the pathogenesis of autoimmunity, and this role was established with the discovery of IL-23 and its function in several IMID, such as psoriasis.
Rahman teaches that intracellular protein phosphatases such as protein tyrosine phosphatase (PTP) play an essential role in T cell receptor (TCR) signaling pathway. The PTPN22 620W allele confers a nearly 2-fold risk for rheumatoid arthritis (page 14, right column, third paragraph), has no association with psoriasis, and appears to be protective for Crohn’s disease. Rahman concludes (page 14, right column, fourth paragraph) that these contrasting patterns are likely to reflect fundamental similarities and differences in the mechanisms underlying the pathogenesis of IMID.
Rahman teaches that dysfunctioning in lymphoid PTP lyp signaling is implicated in 4 autoimmune diseases, including type 1 diabetes, and RA (page 14, right column, fifth paragraph). Rahman further teaches the role of transcription factors such as STAT4 for the pathogenesis of IMID (page 15-16), the role of Th17 cytokines in inflammation and autoimmunity (page 17). For example, Rahman teaches that Th17 cells have been implicated in the pathogenesis of psoriasis, dermal localization of Th17 cells was documented in atopic dermatitis, IL-23 and Th17 cells play a major role in the pathogenesis of IBD, and IL-23 has been implicated in the pathogenesis of RA.
Rahman further teaches (page 18) that environmental factors such as smoking, diet, stress, microbial agents, are essential components of the pathogenesis of several inflammatory diseases such as IBD, psoriasis, RA.
Li et al. (Cell Death and Disease 2020, 11, 932, cited in PTO-892) teach (page 2 of 12, left column, third paragraph) that the term inflammaging describes the condition of chronic sterile low-grade inflammation observed in older organisms. Inflammaging is the long-term result of chronic physio logical stimulation of the immune system, and possess various cellular and molecular mechanisms, including cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, and gut microbiota dysbiosis (Fig. 1).
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In view of the teachings of Rahman and Li, and the complexity of the mechanisms of the different diseases, the genetic predisposition to dysregulation of different pathways that define clinical subgroups of disease, a skilled artisan would view that it is unlikely that the claimed method would be useful for treating the full scope of disorders encompassed by the instant claim 1. Furthermore, as the etiology of the different disorders of instant claim 1 is typically multi-factorial, differing from one condition to another, or can be inherited, it is unlikely that a skilled artisan would view that a compound of instant claim 1 of the instant application could be used to treat the full scope of inflammatory diseases listed in claim 1.
(5) The relative skill of those in the art:
The level of skill in the art is that of the authors of the references cited to support the examiner’s position (MDs, PhDs, or those with advanced degrees and the requisite experience in drug discovery research).
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the instant method is effective in treating the full scope of conditions selected from inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis, psoriasis, pulmonary fibrosis, and systemic sclerosis, as claimed. The Specification has provided guidance for one compound of the invention, serine butyrate, as being effective, upon prophylactic and therapeutic administration, in a murine model of multiple sclerosis, EAE (Example 2, Specification, pages 26-28, Figures 5, 6B, 6C, 8).
However, the specification does not provide guidance for treatment of broadly claimed diseases selected from inflammatory bowel disease (IBD), multiple sclerosis (MS), a neuroinflammatory condition, food allergies, rheumatoid arthritis (RA), asthma, celiac disease, non-alcoholic steatohepatitis (NASH), diabetes, Alzheimer's disease (AD), inflammaging, beta- hemoglobinopathies, vascular inflammatory conditions, atopic dermatitis, psoriasis, pulmonary fibrosis, and systemic sclerosis, with a compound of instant claim 1.
(8) The quantity of experimentation necessary:
Considering the diversity of diseases claimed, the complexity of the underlying mechanisms, and the high unpredictability in the art as pointed out by Rahman et al., one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of claims 1, 9-16, 19, 22-28 and 31.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 9-16, 19, 22-28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Ganapathy et al. (US 2009/0123388, cited in IDS).
Ganapathy (US 2009/0123388) teaches (Abstract) O-butyryl-L-serine (alternative name serine butyrate; structure in Example 5, [0165]) below
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, which is the very compound of the instant claims,
as a preferred prodrug [0072] used for the treatment of, for example, inflammatory bowel disease (one of the 7 diseases listed in the Abstract).
Ganapathy teaches that the compound above is a prodrug [0065], which is consistent with the compound being labile in vivo, as in instant claim 9.
Ganapathy teaches (claim 11) prodrugs of short chain fatty acid attached to an amino acid through a hydroxyl group of said amino acid to form a fatty acid ester of said amino acid; the short chain fatty acid is butyrate (claim 3); the amino acid is, for example, serine, threonine, or tyrosine (claim 10). The genus of Ganapathy encompasses the compounds in instant claim 1, as prodrugs of butyrate with serine, threonine or tyrosine.
Ganapathy teaches [0083] administering a daily dose of 0.1 to 100 mg/kg/day, which encompasses the range in instant claim 19, and overlaps with the ranges in instant claims 25-27.
Ganapathy teaches [0083] administering a total dosage of between 70 mg and 2100 mg per day, which overlaps with the ranges in instant claims 16, 22, 23, 25.
Ganapathy teaches pharmaceutical compositions comprising prodrugs of the invention, as a solution, or tablet [0075], as in instant claim 31, for oral administration [0082] in the method of treatment.
Ganapathy teaches that the patient treated is a human [0073], as in instant claim 14.
Ganapathy does not teach that the daily dose is administered for at least 30 days, as in instant claim 13, nor does he teach twice a day administration, as in instant claims 24, 28.
It would have been obvious for a person of ordinary skill in the art to use the teachings of Ganapathy to treat inflammatory bowel disease with serine butyrate, or tyrosine butyrate or threonine butyrate. The person of ordinary skill in the art would have been motivated to administer serine butyrate to treat inflammatory bowel disease, because Ganapathy teaches that serine butyrate is a preferred prodrug effective to treat, for example, inflammatory bowel disease. Thus, the person of ordinary skill in the art would have administered serine butyrate to a subject suffering from inflammatory bowel disease, with a reasonable expectation of achieving therapeutic effect. Further, the person of ordinary skill in the art would have prepared other prodrugs of butyrate with amino acids, namely prodrugs of butyrate attached to threonine or tyrosine through a hydroxyl group of said threonine or tyrosine to form an ester, because Ganapathy teaches such compounds as prodrugs of the invention, effective to treat, for example, inflammatory bowel disease.
Further, regarding claims 12, 13, 24, 28, the person of ordinary skill in the art would have used the amount/dose taught by Ganapathy, and would have explored different dosing intervals/frequency of administration, such as such as 2 times a day, or one time a day, and different length of treatment, because determining the dosing interval/frequency of administration, and length of treatment with the aim of optimizing therapeutic effect, is routine, well within the skill of the artisan.
As such, claims 1, 9-16, 19, 22-28 and 31 are rejected as prima facie obvious.
Claims 1, 9-16, 19, 22-28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Gold et al. (US 2020/0289442, cited in IDS) and Ganapathy et al. (US 2009/0123388, cited in IDS).
Gold (US 2020/0289442) teaches that butyrate, other butyrate ester prodrugs are effective to treat multiple sclerosis.
Gold teaches a method of treating an autoimmune related disease which is multiple sclerosis ([0017], [0008]) by administering orally to a subject in need thereof a composition comprising propionic acid or butyric acid, or their physiologically acceptable salts or esters ([0008], [0019]).
Gold exemplifies treating multiple sclerosis with propionate in a mouse model of MS (EAE model). Gold teaches [0029] that mice treated with propionic acid showed changes of the microbiota accompanied by increase in the number of regulatory T cells (CD4+CD25+ Foxp3+ Treg). Gene expression profiling of signature cytokines showed increased values with respect to TGFβ, IL-10 generally anti-inflammable messengers—and Foxp3 in mice with experimental autoimmune encephalomyelitis (EAE) fed propionic acid. [0030] Mice fed a propionic acid enriched diet showed in the EAE model a significant significant increase of TGFβ1, IL-10, and Foxp3. These results showed that, in mice that were prophylactically given propionic acid, a significant improvement was observed. Gold teaches [0031] that propionic acid is able to change-and normalize a compromised balance occurring between Treg and effector T cells (Th1/Th17); MS patients show such a disturbed balance.
Gold teaches ([0039], Example 2) that administration of propionic acid showed a significant improvement on the relative axonal density, the demyelination of the white matter, and the number of CD3+-cells (FIG. 3), compared to the control group.
Gold also teaches salts of propionic or butyric acids, [0021] sodium or potassium being especially preferred (sodium butyrate, claim 15); [0022] regarding esters, preference is given to methyl and ethyl esters.
Gold teaches [0024] pharmaceutical compositions in the form of tablets, as in instant claim 31.
Gold teaches [0025] tablets contain a unit dose of 0.2 to 5 g, in particular of 0.5 to 3 g, which overlaps with the range in instant claims 16, 22, 23, 25, 26.
Gold teaches [0026] that the butyrate or propionate are administered in a total daily dose of about 0.2 g to about 10 g (claim 22), which encompasses the ranges/amounts in instant claims 16, 22, 23, 25-27.
Gold teaches that the subject treated is a human (claim 18), as in instant claim 14.
Gold does not teach a method of treating multiple sclerosis with the instant compounds.
Ganapathy (US 2009/0123388) teaches (Abstract) O-butyryl-L-serine (alternative name serine butyrate; structure in Example 5, [0165]) below
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, which is the very compound of the instant claims,
as a preferred prodrug [0072] of butyrate.
Ganapathy teaches that the compound above is a prodrug [0065], which is consistent with the compound being labile in vivo, as in instant claim 9.
Ganapathy teaches (claim 11) prodrugs of short chain fatty acid attached to an amino acid through a hydroxyl group of said amino acid to form a fatty acid ester of said amino acid; the short chain fatty acid is butyrate (claim 3); the amino acid is, for example, serine, threonine, or tyrosine (claim 10). The genus of Ganapathy encompasses the compounds in instant claim 1, as prodrugs of butyrate with serine, threonine or tyrosine.
Ganapathy teaches [0083] administering a daily dose of 0.1 to 100 mg/kg/day, which encompasses the range in instant claim 19, and overlaps with the ranges in instant claims 25-27.
Ganapathy teaches [0083] administering a total dosage of between 70 mg and 2100 mg per day, which overlaps with the ranges in instant claims 16, 22, 23, 25.
Ganapathy teaches pharmaceutical compositions comprising prodrugs of the invention, as a solution, or tablet [0075], as in instant claim 31, for oral administration [0082] in the method of treatment.
Ganapathy teaches that the patient treated is a human [0073], as in instant claim 14.
Ganapathy does not teach that the daily dose is administered for at least 30 days, as in instant claim 13, nor does he teach twice a day administration, as in instant claims 24, 28.
Ganapathy does not teach a method of treating multiple sclerosis with serine butyrate, as in the instant claims.
It would have been obvious to combine the teachings of Gold and Ganapathy to arrive at the instant invention. The person of ordinary skill in the art would have administered serine butyrate to a subject suffering from multiple sclerosis, because Ganapathy teaches that serine butyrate is a butyrate prodrug (which is hydrolyzed in vivo to butyric acid, which is active as an HDAC inhibitor), and Gold teaches that butyrate, other butyrate prodrugs are effective to treat multiple sclerosis. Thus, the person of ordinary skill in the art would have administered serine butyrate to a subject suffering from multiple sclerosis, with the expectation that, upon administration, serine butyrate will be converted in vivo into butyrate, which is effective to treat multiple sclerosis.
Further, the person of ordinary skill in the art would have prepared other prodrugs of butyrate with amino acids, namely prodrugs of butyrate attached to threonine or tyrosine through a hydroxyl group of said threonine or tyrosine to form an ester, because Ganapathy teaches such compounds as butyrate prodrugs. The person of ordinary skill in the art would have administered such threonine or tyrosine butyrate prodrugs to a subject suffering from multiple sclerosis, because Ganapathy teaches that such butyrate prodrugs are hydrolyzed in vivo to butyric acid, and Gold teaches that butyrate, other butyrate prodrugs are effective to treat multiple sclerosis. Thus, the person of ordinary skill in the art would have administered threonine or tyrosine butyrate to a subject suffering from multiple sclerosis, with the expectation that, upon administration, said threonine or tyrosine butyrate will be converted in vivo into butyrate, which is effective to treat multiple sclerosis.
Further, regarding claims 12, 13, 24, 28, the person of ordinary skill in the art would have used the amount/dose taught by Gold and Ganapathy, and would have explored different dosing intervals/frequency of administration, such as such as 2 times a day, or one time a day, and different length of treatment, because determining the dosing interval/frequency of administration, and length of treatment with the aim of optimizing therapeutic effect, is routine, well within the skill of the artisan.
As such, claims 1, 9-16, 19, 22-28 and 31 are rejected as prima facie obvious.
Conclusion
Claims 1, 9-16, 19, 22-28 and 31 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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