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 office acknowledges Applicants response filed on 12/19/2025 in regards to the restriction election requirement dated 10/21/2025. Applicants have elected Group I with traverse. Applicants argue that a search for the methods recited in Group I would likely also uncover art relevant to the methods of Group II, both of which comprise administering 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenylmethyl]-1,3-thiazolidine-2,4-
dione, or its salt’ any additional searches that would be needed would not be a serious burden on the Examiner and have also recited MPEP § 803. Applicant has provisionally elected adrenoleukodystrophy (ALD or X-ALD) as the disease or disorder to be treated or prevented with traverse. Applicants argue that a search of the elected species would likely uncover art relevant to the additional diseases and disorders recited in the claims; any additional searches that would be needed would not be an undue burden on the Examiner.
In response, Applicants arguments have been fully considered. However Group I claims are to a method of treating and prevention of disorders and Group II is to administering the agent to a patient, measuring biomarkers, adjusting the therapeutic concentrations. Group I involves treating or prevention which requires additional/ different steps to carry out the method based on specific conditions to be treated. Group II involves steps that are different than that of Group I. Group II requires administration of the agent to any patient in need thereof and measuring the PPAR-y engagement biomarker and titration of the dosage amounts. The inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, and/or employing different search strategies).There may be overlap in the searches but the methods are to different processes and involves different steps and would be a serious search burden to the examiner. Further the inventions may likely raise serous examination issues such as non-prior art issues under 35 US 101 and/or 112(a). Further group I involves prevention of disease or disorders in subjects which may involve enablement and or written description issues.
As to the species, each disease that has been claimed to be treated has a different and distinct etiology and pathophysiological manifestations, and that each is differently treated. For example, thyroid carcinoma is a distinct disorder and is not related to nonalcoholic fatty liver disease. Applicants have listed hundreds of diseases in claim 53. Disease states herein claimed do not flow from a single biochemical lesion, but form a range of physiological activities. Such is sufficient to indicate that each of the methods of treating the presently claimed disease states is differently searched in the patent and non-patent literature and that a search for one disease will not necessarily result in a comprehensive search of any one or more of the diseases listed. As a result, an undue burden would be placed on the Examiner to search each of Applicant's presently claimed species. MPEP 809.02(d) states "[w]here only generic claims are presented, no restriction can be required except in those applications where the generic claims recite such a multiplicity of species that an unduly extensive and burdensome search would be necessary if all claimed species were to be examined simultaneously. Hence the restriction requirement election is maintained. The restriction requirement is made final.
Claims 3, 16, 18, 28, 29, 40-44, 53, and 62-75 are pending. Claims 28, 29, 40-44, 71-75 read on the elected group and/or species. Claims 3, 16, 18, 53, 62-70 are withdrawn from further consideration pursuant to 37 C.F.R. 1.142(b), as being drawn to non-elected subject matter. Claims 28, 29, 40-44, 71-75 have been examined to the extent that they read on the elected subject matter.
Application Priority
This application filed 09/01/2023 is a divisional of 16972366, filed 12/04/2020, 16972366 is a National Stage entry of PCT/IB2019/054744, International Filing Date: 06/06/2019, claims foreign priority to 18382402.8, filed 06/06/2018.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 4/11/2024 and 12/19/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
Claim Rejections - 35 USC § 112
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 71-75 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 plasma pharmacokinetics of M-III, MIV, Mitochondrial pyruvate carrier (MPC) inhibitory activity of MIN-102, effect of MIN-102 on adiponectin, effects of MEN-102 in the Methionine Choline Deficient Diet Fed Mice, strong reduction in liver steatosis and inflammation in MCD mice treated with MIN-102, the specification does not reasonably provide enablement for prevention of all diseases that is claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMWofN. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the breadth of the claims, 3) the predictability or lack thereof in the art, 4) the state of the prior art, 5) the presence or absence of working examples, 6) the amount of direction or guidance present, 7) the relative skill of those in the art and 8) the quantity of experimentation needed. The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
(1)/(2) The nature of the invention & breadth of claims:
The examined claims are directed to:
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Applicants define, “The term "prevention" or "to prevent" refers to the reduction in the risk of acquiring or developing a given disease or disorder, or the reduction or inhibition of the recurrence or a disease or disorder” [0177]. Accordingly, the risk of acquiring or developing a disease is preventing the disease from occurring in any subject.
In general, the term "prevention" may vary widely in meaning, from "preventing" from occurring to "preventing" it from progressing. Nor is the term limited by any time frame. The claim is very broad insofar as they suggest that the subject will not experience the disease or disorder ever again when taking the claimed agent; that should one get the disease, it will not worsen; or that following its treatment, it will not recur. While such "prevention" might theoretically be possible under strictly controlled laboratory conditions, as a practical matter it is nearly impossible to achieve in the "real world" in which patients live.
The claims are broad in respect to the diseases to be prevented.
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The elected disease to be prevented is adrenoleukodystrophy (ALD), a neurodegenerative disease. ALD is a rare genetic condition caused by genetic variants in the ABCD1 gene, which prevent the body from transporting very-long-chain fatty acids and it cannot be prevented (See Cleveland Clinic, https://my.clevelandclinic.org/ health/diseases/6030-adrenoleuko dystrophy-ald, 2026).
(3)/(4) predictability in the art & the state of the prior art:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. More generally, the invention is directed toward medicine and is therefore physiological in nature. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved". See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
It is not predictable from the art or from the specification that all conditions as claimed can be prevented. In fact there are no examples in the instant specification providing evidence that the compound(s) used in the method(s) was administered and a condition associated with CNS disorder was prevented before occurring. For example, the elected disorder, adrenoleukodystrophy (ALD) is a genetic condition that cannot be prevented. It is caused by mutations in the ABCD1 gene, which are inherited in an X-linked manner.
Cleveland Clinic teach that “There is no known way to prevent ALD. If a family member has ALD, follow your provider’s recommendation for genetic testing and counseling” (See https://my.clevelandclinic.org/health/diseases/6030-adrenoleuko dystrophy-ald, 2026).
According to Mayo Clinic, adrenoleukodystrophy has no cure. However, stem cell transplantation may stop the progression of ALD if done when neurological symptoms first appear (https://www.mayoclinic.org/diseases-conditions/adrenoleukodystrophy/ diagnosis-treatment/drc-20369160, 2026).
(5)/(6) Amount of guidance/working examples:
Applicants have provided guidance to plasma pharmacokinetics of M-III, MIV, Mitochondrial pyruvate carrier (MPC) inhibitory activity of IVN-102, effect of MIN-102 on adiponectin, effects of MEN-102 in the Methionine Choline Deficient Diet Fed Mice, strong reduction in liver steatosis and inflammation in MCD mice treated with MIN-102.
The state of the art teach that ALD is a rare genetic condition caused by genetic variants in the ABCD1 gene, which prevent the body from transporting very-long-chain fatty acids and it cannot be prevented. There is no guidance in the instant specification or in the art for prevention of elected condition, ALD.
There are no working examples towards prevention of the diseases as claimed including the elected disease, ALD. One of ordinary skill in the art will not be able to extrapolate the data provided in the specification and in the prior art towards preventing various types of conditions for e.g. CNS conditions, neurodegenerative diseases etc.
(7) The relative skill of those in the art:
The relative skill in the art is fairly high, with the typical practitioner having a medical degree and/or an advanced degree in the biochemical, chemistry or pharmaceutical-related arts.
(8) The quantity of experimentation needed:
Since the guidance and teaching provided by the specification is insufficient for preventing all the diseases as claimed one of ordinary skill in the art, even with high level of skill, will be unable to use the 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl] methyl]-1,3-thiazolidine- 2,4-dione in preventing the conditions as claimed without undue experimentation. The level of experimentation required in order to practice the claimed invention would be undue. A person of ordinary skill in the art first have to test the formulation in prevention of the claimed disease(s) to determine the efficacy of the agent in vitro and then test in vivo. Thus, in order to practice the claimed invention, one of ordinary skill in the art would have to first envision formulation, dosage, duration, route and, in the case of human treatment, an appropriate animal model system to test the substrates to determine whether or not it is useful for treating all the diseases as in the instant claims. If unsuccessful, one of ordinary skill in the art would have to envision a modification in the formulation, dosage, duration, route of administration etc. and appropriate animal model system, or envision an entirely new combination of the above and test the system again. Considering the above-mentioned factors and the fact that there is significant inter- individual variability in using pharmacological modalities in human subjects, the nature of art is unpredictable, and the breadth of the claims; one of ordinary skill in the art would be burdened with undue "experimentation study" to determine the dosage amounts and the specific disorder is being treatable or not. Therefore, it would require undue, unpredictable experimentation to practice the claimed invention. MPEP 2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 28-29, 40-44, 71-75 are rejected under 35 U.S.C. 103 as being unpatentable over Garcia Collazo et al. (US 20160235729) and Kawaguchi-Suzuki et al. (J of Chromatography, 2014, 219-223).
Garcia Collazo et al. teach the use of 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy) benzyl)thiazolidine-2,4-dione (MIV) in the treatment of adrenoleukodystrophy (ALD) (See claims 28 and 35). The reference teaches that this compound is MIV, and it is a metabolite of compound pioglitazone [0019]. The reference teaches pioglitazone’s utility has been demonstrated in the treatment of X-ALD based on pre-clinical data (US2013/0274295). It is taught that clinical trials using pioglitazone for ALD have failed to show clinical benefits and the drug has been associated with unwanted side effects including cardiovascular effects, fluid retention, weight gain and bladder cancer ([0015], [0016]). Further taught is that the compound MIII is also a metabolite of pioglitazone [0018].
The structures of pioglitazone and its metabolites MIV and MIII are given below in table 1. Garcia Collazo is explicit in teaching that the metabolite MIV is useful in treating ALD.
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It is noted that MIII is 5- [[4-[2-[5-acetylpyridin-2-yl]ethoxy] phenyl]methyl]-1,3-thiazolidine-2,4-dione (the compound administered in the instant claims) and MIV is 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy) benzyl)thiazolidine-2,4-dione.
The reference teaches that a typical daily dosage is from 0.1 to 200 mg, preferably from 20 to 200 mg, e.g. for an adult 10-100 mg given as a single dose with no further dosing or in multiple doses, for example one to three times per day. The compounds described herein may also be administered in daily doses of from 80 to 600 mg. The dose of the active agent will depend on the nature and degree of the condition, the age and condition of the patient, and other factors known to those skilled in the art [0076]. The reference teaches oral administration and the dosage form include suspensions ([0075], claims 48-49). Exemplary pharmaceutically acceptable salts include the salts of hydrochloric acid [0072].
Kawaguchi-Suzuki et al. teach that hydroxypioglitazone and ketopioglitazone are active metabolites of pioglitazone (page 220, Fig. 1).
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It is noted that hydroxypioglitazone is MIV and ketopioglitazone is MIII compound.
The prior art do not teach treating ALD with the compound 5- [[4-[2-[5-acetylpyridin-2-yl]ethoxy] phenyl]methyl]-1,3-thiazolidine-2,4-dione (MIII) as in the instant claims.
A person skilled in the art would have found it obvious before the effective filing date of the invention from Garcia Collazo that (i) the compound used in the instant claim, 5- [[4-[2-[5-acetylpyridin-2-yl]ethoxy] phenyl]methyl]-1,3-thiazolidine-2,4-dione, is the compound MIII and it is a metabolite of pioglitazone and (ii) another metabolite of pioglitazone, MIV (5-(4-(2-(5-(1-hydroxyethyl) pyridine-2-yl)ethoxy) benzyl)thiazolidine-2,4-dione) is used in the method of treating ALD (iii) the parent compound pioglitazone has been associated with side effects and have failed to show positive results in clinical trials in regards to treating ALD (iv) Kawaguchi-Suzuki teach that hydropioglitazone (MIV) is converted to MIII (See Fig. 1). From the prior art teachings a person skilled in the art would have found it obvious to use metabolite MIII for metabolite MIV of pioglitazone to treat ALD. A person skilled in the art would have been motivated to do so is to achieve similar or better therapeutic benefits compared to the MIV compound in subjects with ALD. As to the limitation of wherein compound MIII is metabolized to compound MIV, it is noted that administration of the same agent (effective amount, e.g. 50 mg) to the same set of patients would result in the same effects including the parent (MIII) metabolized to 5-[[4-[2-[5-(1-hydroxyethyl) pyridin-2-yl]ethoxy]phenyl]methyl]-1,3- thiazolidine-2,4-dione (MIV).
As to the effective amount, the instant specification teach “By an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation” [0337]. Thus, the dose of the active agent will depend on the nature and degree of the condition, the age and condition of the patient, and other factors known to those skilled in the art. A typical daily dose of Compound (1), or a pharmaceutically acceptable salt, for an adult is from about 10 mg to about 500 mg [0380].
From Garcia Collazo a skilled artisan would have found it obvious to administer an effective amount, e.g. 10-500 mg of compound MIII (a metabolite of pioglitazone) orally to treat ALD in patients. As to the parameters, AUC, Cmin would be achieved upon administration of the same agent as claimed in the same effective amount to the same set of subjects, herein ALD in the administration dosage regimen as claimed. Further the AUC and concentration are well-known results effective variables in the art as evidenced by use in the cited reference (Collazo, p 10, [0125-0129], figs. 1-3). The dosage regimen of administration of at least 5 days is within the skill of an artisan (e.g. physician) based on the health condition and other factors and it is routine. Thus claims 28-29, 42-44 would have been obvious over the prior art Garcia Collazo. As to claim 40, the prior art teach the use of pharmaceutically acceptable HCl salt. Hence a skilled artisan would have found it obvious to use the HCl salt of the compound of instant claim 28 to treat ALD subjects. As to claim 41, the prior art teach using suspensions of the compound MIV for oral administration and the dosage amount ranging from 10-500 mg. Hence a skilled artisan would have found it obvious to administer a suspension comprising MII, 5-15 mg (the compound of the instant claims) to treat ALD. As to claims 71-75 a person skilled in the art would have found it obvious from Garcia Collazo to administer orally an effective amount (e.g. 50 mg- 500 mg) of compound MIII to subject with ALD, for e.g. once per day. A skilled artisan would have been motivated to arrive at the claimed method is with a reasonable amount of success and to provide therapeutic benefits to ALD patients. As to the limitations of the active agent administered is being metabolized to MIV administration of the same agent in an effective amount with the same dosage regimen to the same set of patients, herein ALD would result in the same pharmacokinetic effects when measured after 5 days. It is obvious that administration of the same agent to the same set of subjects with an effective amount (for e.g. 50-500 mg as in instant claim 75) would result in the same plasma concentrations as instantly claimed. Further a skilled artisan would have measured the plasma concentrations after specific dosage regimen is to evaluate the effectiveness of the medication, measure therapeutic window, for personalized dosing and to monitor the stability by maintaining a stable plasma concentration. Thus the claimed methods would have been obvious over the prior art teachings.
Note: The scope of enablement rejection on claims 3, 28 and 71 and its depending claims for the treatment of myriad of diseases with 5- [[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione has not been made as the examination in this action has been made based on the elected species.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 28-29, 40-44, 71-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 18, 20-22 of U.S. Patent No. 9782395 (‘395) or claims 1-4, 6, 7, 8, 19-24, 26 of US 10179126 (‘126) in view of Garcia Collazo et al. (US 20160235729) and Kawaguchi-Suzuki et al. (J of Chromatography, 2014, 219-223).
The instant methods are directed to:
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The dependent claims are limited to specific pharmacokinetic parameter amounts, salt of the active agent, oral suspension and amount, plasma concentration and specific genus and sub-genus of disorders to be treated.
‘395 reference claims are directed to a method of treatment of a central nervous system disorder, comprising administering to a subject in need thereof a dosage form comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the central nervous system disorder is adrenoleukodystrophy (ALD or X-ALD.
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The dependent claims are limited to specific stereoisomers, dosage amount (0.1-200 mg), and dosage forms.
‘126 reference claims are directed to a method of treatment of a central nervous system disorder, comprising administering to a subject in need thereof a dosage form comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the central nervous system disorder is selected from the group consisting of a neurodegenerative disease, including leukodystrophy.
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The dependent claims are limited to specific genus and sub-genus of disorders to be treated, oral dosage form that includes an oral suspension.
The refernece claims do not teach treating ALD with the active agent as in the instant claims.
Garcia Collazo et al. teachings discussed as above.
A person skilled in the art would have found it obvious before the effective filing date of the invention would have found it obvious to arrive at the claimed invention from the reference claims and prior art because (i) reference claims and the prior art teach 5-(4-(2-(5-(1-hydroxyethyl) pyridine-2-yl)ethoxy) benzyl)thiazolidine-2,4-dione) in treating ALD or leukodystrophy (ii) the prior art is explicit in teaching the metabolites of pioglitazone as 5- [[4-[2-[5-acetylpyridin-2-yl]ethoxy] phenyl]methyl]-1,3-thiazolidine-2,4-dione (MIII) and (5-(4-(2-(5-(1-hydroxyethyl) pyridine-2-yl)ethoxy) benzyl)thiazolidine-2,4-dione) (MIV) and (iii) the parent compound pioglitazone has been associated with side effects and have failed to show positive results in clinical trials in regards to treating ALD (iv) Kawaguchi-Suzuki teach that hydropioglitazone (MIV) is converted to MIII (See Fig. 1). From the combined teachings a skilled artisan would have found it obvious to use metabolite MIII for metabolite MIV of pioglitazone to treat ALD to achieve similar or better therapeutic benefits compared to the MIV compound in subjects with ALD. As to the limitation of wherein compound MIII is metabolized to compound MIV, it is noted that administration of the same agent (effective amount, e.g. 50 mg) to the same set of patients would result in the same effects including the parent (MIII) metabolized to 5-[[4-[2-[5-(1-hydroxyethyl) pyridin-2-yl]ethoxy]phenyl]methyl]-1,3- thiazolidine-2,4-dione (MIV).
As to the effective amount, the instant specification teach “By an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation” [0337]. Thus, the dose of the active agent will depend on the nature and degree of the condition, the age and condition of the patient, and other factors known to those skilled in the art. A typical daily dose of Compound (1), or a pharmaceutically acceptable salt, for an adult is from about 10 mg to about 500 mg [0380].
From Garcia Collazo a skilled artisan would have found it obvious to administer an effective amount, e.g. 10-500 mg of compound MIII (a metabolite of pioglitazone) orally to treat ALD in patients. As to the parameters, AUC, Cmin would be achieved upon administration of the same agent as claimed in the same effective amount to the same set of subjects, herein ALD in the administration dosage regimen as claimed. Further the AUC and concentration are well-known results effective variables in the art as evidenced by use in the cited reference (Collazo, p 10, [0125-0129], figs. 1-3). The dosage regimen of administration of at least 5 days is within the skill of an artisan (e.g. physician) based on the health condition and other factors and it is routine. Thus claims 28-29, 42-44 would have been obvious over the prior art Garcia Collazo. As to claim 40, the prior art teach the use of pharmaceutically acceptable HCl salt. Hence a skilled artisan would have found it obvious to use the HCl salt of the compound of instant claim 28 to treat ALD subjects. As to claim 41, the prior art teach using suspensions of the compound MIV for oral administration and the dosage amount ranging from 10-500 mg. Hence a skilled artisan would have found it obvious to administer a suspension comprising MII, 5-15 mg (the compound of the instant claims) to treat ALD. As to claims 71-75 a person skilled in the art would have found it obvious from Garcia Collazo to administer orally an effective amount (e.g. 50 mg- 500 mg) of compound MIII to subject with ALD, for e.g. once per day. A skilled artisan would have been motivated to arrive at the claimed method is with a reasonable amount of success and to provide therapeutic benefits to ALD patients. As to the limitations of the active agent administered is being metabolized to MIV administration of the same agent in an effective amount with the same dosage regimen to the same set of patients, herein ALD would result in the same pharmacokinetic effects when measured after 5 days. It is obvious that administration of the same agent to the same set of subjects with an effective amount (for e.g. 50-500 mg as in instant claim 75) would result in the same plasma concentrations as instantly claimed. Further a skilled artisan would have measured the plasma concentrations after specific dosage regimen is to evaluate the effectiveness of the medication, measure therapeutic window, for personalized dosing and to monitor the stability by maintaining a stable plasma concentration. Thus the claimed methods would have been obvious over the reference claims and the prior art teachings.
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 3, 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3 and 42 recite a limitation of ‘an inflammation and autoimmune disease’ in line 8 (claim 3) and in line 6 (claim 42). It is well known that inflammation and autoimmune diseases are disorders by itself. The instant specification does not define that both ‘an inflammation and autoimmune disease’ are one disorder or separate disorders to be treated. Is it inflammation associated with an autoimmune disease is treated or both the disorders treated? Clarification is required.
Conclusion
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/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627