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 .
Priority
The instant application claims priority as follows:
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Claims 17-34 are currently pending and are the subject of this Office Action.
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.
Claim 31 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 17-21, 24, 28-30, 33 and 34 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Overkleeft et al. (WO 2015/147639-cited in the ISR received on 07/09/2024), as evidenced by Plotegher et al. (Trends in Molecular Medicine, February 2017, Vol. 23, No. 2; p. 116-134) or Pyeritz, R. E., Korf, B. R., & Grody, W. W. ((2020). Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Metabolic Disorders. Elsevier Science & Technology, Chapter 14.3.1).
Plotegher and Pyeritz references are only used as evidentiary references to show that Tay-Sachs disease and Sandhoff disease are GM2 gangliosidoses, where a deficiency of β-hexosaminidase (HEXB) functionality, hexosaminidase A or B, respectively, leads to the accumulation of GM2 ganglioside. See at least Plotegher at page 117.
Overkleeft teaches N-substituted deoxynojirimycin derivatives that are effective in the treatment of Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and chronic inflammation (see at least abstract). A “highly preferred” compound has the formula
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(at least page 34), which is the same as the compound in free base form of the instant claims. The reference teaches that the invention comprises pharmaceutically acceptable hydrates that are crystals comprising the compound (p. 28) and pharmaceutical compositions comprising the compound (p. 82-85). The compound is administered as a daily dose (see p. 84).
An amount effective for the treatment by oral administration was disclosed to be at least in the range of
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, which, for an average body weight of an adult patient (60-80 kg) would be from 6 mg-800 mg a day of the compound (p.84).
Since Overkleeft taught the treatment of the GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease with the same exact compound of the claims, the treatment would necessarily result in increasing survival of the treated subject at the life expectancy instantly claimed in claim 24, and providing the therapeutic benefit of instant claim 30 to the treated subject, and reducing inflammation in the subject. That is because the identical compound administered to the identical subject (a patient suffering from the GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease) must inherently have the same claimed effect, even if not recognized in the art, since products of identical chemical composition cannot have mutually exclusive properties when administered under the same circumstances, and to the same host.
MPEP 2112: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.” Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). "[W]hen considering a prior art method, the anticipation doctrine examines the natural and inherent results in that method without regard to the full recognition of those benefits or characteristics within the art field at the time of the prior art disclosure." Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1377-78 (Fed. Cir. 2005) ("In some cases, the inherent property corresponds to a claimed new benefit or characteristic of an invention otherwise in the prior art. In those cases, the new realization alone does not render the old invention patentable."). See also MEHL/HIophile Int’l Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999).
A newly-discovered result or property of an existing (or obvious) method of use is not patentable. See Abbott Labs. v. Baxter, 471 F.3d at 1368-69. Also, MPEP §2112.02: “However, when the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated.”
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.
Claim(s) 20-21, 25-27, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Overkleeft et al. (WO 2015/147639-cited in the ISR received on 07/09/2024) as applied to claims 17-21, 24, 28-30, 33 and 34 above, and further in view of Jeyakumar (Ann Neurol 2004; 56: 642-649- cited in the ISR received ).
Overkleeft
The teachings of Overkleeft discussed above are incorporated herein by reference.
Overkleeft additionally teaches that the compound can be “used in combination with various therapeutic or prophylactic agents for the diseases for which the compound is considered to be effective.” “The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval” and is administered in a daily dose. See page 84-85.
Regarding the effective amounts, the reference teaches the following at p. 84-85:
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If we assume the average body weight to be between 60-80 kg then, the reference range of
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would be 6 mg-800 mg.
Regarding the pH of the pharmaceutical composition comprising the compound, the reference teaches that “a known excipient, and also a pH adjusting agent” may be appropriately added thereto (p. 84).
Jeyakumar
Jeyakumar teaches a survival increase when non-steroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of Sandhoff disease in mice. Further, Jeyakumar disclosed that a combined therapy with NSAID and substrate reduction therapy drugs (SRT) resulted in synergy. See at least the abstract:
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Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 20-21, while Overkleeft taught the free base of the pharmaceutical compound in the form of a crystal hydrate, it would have been obvious to make any crystalline form of the free base of said pharmaceutical compound. It is well known that crystalline materials can produce better pharmaceuticals. US 5,721,359 says, “Crystalline materials are preferred in most pharmaceutical applications. Crystalline forms are thermodynamically more stable than amorphous forms of the same substance.” US 7,145,002 notes, “Crystallization allows isolation of a compound with rejection of impurities, and crystalline forms tend to be more stable than amorphous forms of the same compound.” US 4,432,987 notes, “Crystalline forms of compounds are ordinarily preferable to the non-crystalline forms thereof. The crystalline materials have superior stability, appearance and handling characteristics when compared to their amorphous counterparts. For pharmaceutical use crystalline compounds are especially advantageous.” Morissette teaches in general that “the preferred solid form is generally the thermodynamically most stable crystalline form of the compound” and that “it is incumbent on the innovator of a new drug candidate to identify and patent these forms in order to optimally protect their investment in the compound.” Such observations have been made for more than 30 years. Hence, one of ordinary skill in the art would have been well motivated to crystallize the drug of the primary reference (nizubaglustat, AZ-3102) to obtain the advantages of the crystalline form and to use the crystalline form for the same use that the old drug is known for.
With respect to claims 25 and 31, the goal of administering the drug is to provide treatment to the patient afflicted with Tay-Sachs and Sanhoff disease (GM2 gangliosidosis). Jeyakumar discussed that GM2 ganglioside (Tay-Sachs and Sanhoff disease) is due to inherited defects in the genes, and most affected individuals die in early childhood. The afflicted patient may be a baby, a child, a teenager or an adult, and therefore, it would have been obvious to treat a patient of the age between 28 days and 30 years of age that is suffering from said diseases. It would have been prima facie obvious to one having ordinary skill in the art to find the best and appropriate dosages of the compound to treat Tay-Sachs and Sanhoff disease (GM2 gangliosidosis) in the afflicted patients. This would depend on at least the weight of the patient, the age of the patient, any other conditions the patient may have, the mode of administration, etc. In the instant case, the dose of the compound administered to the patient is considered a result-effective variable that impacts the effectives of the treatment, and which the artisan knows how to optimize. Note that Overkleeft taught various dosage ranges and stated that “the dose is appropriately decided upon in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.” Differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization. The dosage in instant claim 25 would have been obvious.
With respect to claims 26 and 27, Overkleeft taught that the claimed compound
can be “used in combination with various therapeutic or prophylactic agents for the diseases for which the compound is considered to be effective.” “The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval” and is administered in a daily dose. See page 84-85. It would have been prima facie obvious to combine the claimed compound with an NSAID, as Jeyakumar taught that the treatment of GM2 ganglioside with an NSAID alone, and in combination with SRT, results in a significantly slowed clinical course, and that synergy resulted from the combination.
In addition, it has been held that “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.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06.
With respect to claim 32, Overkleeft taught pharmaceutical compositions of the compound with excipients and other agents for various administration routes. In the instant case, the pH of a pharmaceutical composition is considered a result-effective variable that influences stability, solubility, absorption, and safety of the drug. However, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. A person having ordinary skill is capable of optimizing the pH of a pharmaceutical composition through routine experimentation using conventional techniques in the art. Absent a showing of criticality, optimizing result-effective variables is deemed routine optimization.
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 20-23 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.
The scope of the rejected claims is that of all and any crystalline form of the compound of formula (I). Claims 22 and 23 further recites that the form is characterized by one of the four strongest reflections, and further one or more reflections at one or more of
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Claims 20-23 do not require that the crystal form be the form described in this application. However, the instant specification is directed to making specific crystal forms, prepared under specific conditions not functional for other crystalline forms. Applicant has shown possession of the crystal forms described in the specification, but has not conveyed that was in possession of any other crystalline form.
Claims 22 and 23 purport to describe the invented crystalline form by the selection of one XRPD peak, or two XRPD peaks. However, one or two peaks are not enough to establish crystal structure identity.
The art knows that generation of polymorphs is unpredictable. It is not obvious from the disclosure how different crystal forms of the combination can be made. The art knows that disclosure of one crystal form cannot represent other crystal forms of the same combination and that one crystal form does not provide support for any other crystal form of the same compound.
Selecting one peak, or two peaks from those described in claim 23, does not properly describe any particular form. Brittain et al. (H Brittain, ed. Polymorphism in Pharmaceutical Solids (1999) p. 235-238) disclosed that identity is established with the ten strongest reflections.
Accordingly, it is deemed that the specification does not describe in sufficient detail the invention and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
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 17-25 and 28-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,116344B2 alone, and claims 26-27 in view of Jeyakumar (Ann Neurol 2004; 56: 642-649). Although the claims at issue are not identical, they are not patentably distinct from each other because there is no patentable distinction between the crystalline compound AZ-3102 as claimed in the patent, and the method of using the crystalline compound AZ-3102, as claimed here. See Mosler Sage & Lock Co. V. Mosler, Bahmann & Co., 127 U.S. 354, 218 S.Ct. 1148 (1888) [The first patent was of an article; the second patent, held invalid, was for a method of making it]. See also Ex parte MacAdams, 206 USPQ 445 [The patent had a composition of matter; the application had the method of use]. While the claims in the patent are directed to the same crystalline compound AZ-3102 and the instant claims are directed to methods, the patent discloses the utility of the compounds and the instant claims claim the same method of using that is described in the specification of the patent.
This rejection is also proper under the recent court decision in Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ 2d 1797. The claims of a later patent were invalid for obviousness-type double patenting because the earlier patent claimed the compound and disclosed its utility in the specification, and the later patent claimed a method of using the patented compound for the use described in the specification of the earlier patent. According to MPEP 804(II)(B)(1), “it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context.”
In addition, a person of ordinary skill in the art is a medical practitioner/professional who knows how to select dosage forms, pharmaceutical composition pH, appropriate dosages, treatment time, dosing schedule, and patient to be treated. The skilled artisan is aware that the appropriate dosing scheme, including amount of drug in each dose, frequency of dosages, total amount of drug per day, will vary depending on the state of the subject and the state of the condition, and the pH of the formulation will vary depending on the stability, solubility, route and desired absorption of the drug. A person of ordinary skill would have been motivated to adjust these parameters as part of routine optimization to determine the optimal amounts needed to treat those diseases disclosed in the patent. Therefore, claims 17-25 and 28-34 are obvious.
Regarding claims 26-27, it would have been prima facie obvious to combine the crystalline compound AZ-3102 as claimed in the patent with a NSAID, as Jeyakumar taught that the treatment of GM2 ganglioside of the patent with an NSAID alone, and in combination with SRT, results in a significantly slowed clinical course, and that synergy resulted from the combination.
In addition, it has been held that “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.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06.
Conclusion
Claims 17-34 are rejected. No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VALERIE RODRIGUEZ-GARCIA/ Primary Examiner, Art Unit 1621
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