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 .
Amended claims 46-67 are pending. Claims 66-67 remain withdrawn.
This is a Non-final rejection.
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.
Claim(s) 46, 47, 55- 63 is/are rejected under 35 U.S.C. 103 as being unpatentable over Olivier US10562930 in view of Schunk US 8404740, Gant US6831091, Kojima, Int J Pharm. 2008 Mar 20;352(1-2):146-51, Morissette, Advanced Drug Delivery Reviews 56 (2004) 275-300, US5762961 and US5958455.
Olivier teaches pharmaceutical compositions of Compound 1, crystalline forms thereof, methods of their preparation, pharmaceutical compositions thereof and methods of their use where the Compound 1, is same as the instant Compound 1.
The difference is that the instant
base claim 1 is drawn to pharmaceutical composition comprising hemi-citrate salt of the Compound 1 as active ingredient
while
Oliver disclosure is drawn to pharmaceutical composition of hydrobromide, citrate, malate, maleate, mesylate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, napthalene-2-sulfonate, ascorbate, oxalate, napthalene-1,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentisate, 1-hydroxy-2-napthoate, dichloroacetate, cyclamate, and ethane-1,2-disulfonate salts, of Compound 1.
Also note as implied by the language of instant claim 47, the instant composition does include Oliver’s citrate salt, also in the context of the open-ended comprising language of instant base claim 46.
The salt forming moiety of Compound 1 is shown below in partial structure
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With two nitrogens for protonation in the imidazole and three acidic groups in citric acid, one of skill in the art would expect salts containing different stoichiometric amount (molar ratio) of citrates (hemi-, mono- and di- citrate) can be made for optimization (more on this later) of physical and chemical properties. More specifically, it is well-known that citric acid and its salts are extensively used in pharmacology to optimize the stability, solubility, and bioavailability of therapeutic drugs. For example, Schunk teaches different salts of basic active ingredients and further prefers citrate and hemicitrate (see column 6 line 56). Similarly, Gant teaches salts with different molar ratio of basic compounds with mono and dibasic acids including hemi-citrate salts. Further Kojima titled ‘Physicochemical properties of tamoxifen hemicitrate sesquihydrate’ teaches how to make citrate and hemi-citrate
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The compounds of Grant and Kojima are pure compounds as ascertained by X-ray crystal structures. Crystallization is routine in the art as part of isolating compounds in pure form. Olivier compounds are X-ray quality having been crystallized and therefore pure. It would have been obvious to one with skill in the art to isolate and purify similar salt forms of a similar formula such as a hemi-citrate salt when utilizing salts which may undergo multiple protonations. Olivier at column 8, first full paragraph teaches that the nature of the salt is not critical provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. In a salt, proton transfer occurs between Compound 1 free base and an organic acid or an inorganic acid. However, in some cases proton transfer is incomplete. In such cases, Compound 1 and the “co-former” molecules in the solid (i.e., “co-crystal”) interact through non-ionic forces such as hydrogen bonding.
The intended use of claimed composition and that of Oliver’s composition is the same.
There is common ground that the biological activity of a compound depends primarily on
its molecular structure. To reach its target it will at some point be in solution, e.g. in body fluids, where all differences among (salts) and polymorphs disappear. The skilled person would thus expect that all polymorphs of the compound display the same pharmacodynamic profile. In addition, the methods to screen for polymorphs are well known in the art as taught by Morissette. According to Morissette (opening statement) “Active pharmaceutical ingredients can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, co-crystals and amorphous solids. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability and other performance characteristics of the drug”.
As noted the composition of Oliver and the instant have the same active ingredient and same utility. According to MPEP 2144.04 [R-07.2022] Pure materials are novel vis-à-vis less pure or impure materials because there is a difference between pure and impure materials. Therefore, the issue is whether claims to a pure material are nonobvious over the prior art. In re Bergstrom, 427 F.2d 1394, 166 USPQ 256 (CCPA 1970). Purer forms of known products may be patentable, but the mere purity of a product, by itself, does not render the product nonobvious. Factors to be considered in determining whether a purified form of an old product is obvious over the prior art include whether the claimed chemical compound or composition has the same utility as closely related materials in the prior art, and whether the prior art suggests the particular form or structure of the claimed material or suitable methods of obtaining that form or structure. In re Coffer, 354 F.2d 664, 148 USPQ 268 (CCPA 1966).
The skilled person investigating the therapeutic application of the Compound 1 (of Oliver) would thus routinely screen for different salts and polymorphs thereof to arrive at pure hemi-citrate salt. If such routine work yields other polymorphs, e.g. the presently claimed ones, then their provision is an obvious.
In the absence of any substantiated unexpected property for secondary considerations, the combined teachings of the above cited art, renders the claims unobvious.
Dependent claims 55- 63 are drawn to excipients and optimization of pharmaceutical compositions and are within the purview of one of skill in the art. For example, see
5762961: claims
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5958455 Likewise, see claims 4, 7, 8, 13, 16 and also column 3 lines 22-48.
Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 46, 47, 55- 63 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. US10562930 (herein after Oliver) in view of Martinez WO2016061527, Schunk US 8404740, Gant US6831091, Kojima, Int J Pharm. 2008 Mar 20;352(1-2):146-51 and Morissette, Advanced Drug Delivery Reviews 56 (2004) 275-300 and Rodriguez, Advanced Drug Delivery Reviews 56 (2004) 241-274 and US5762961 or US5958455.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims overlapping subject matter as explained below.
The difference is:
Claims 1-13 of Oliver are drawn to citrate salt of the Compound 1
Claims 14-120 of Oliver are drawn to hydrobromide salt of the Compound 1
The instant claims are drawn to >95% pure hemi-citrate salt of the Compound 1
Compound 1 itself is taught by Martinez in claim 49 page 252 fourth compound and has the same inherent biochemical property and is also intended for the same CNS pharmaceutical use as per instant claims and conflicting claims.
Oliver disclosure is drawn to pharmaceutical composition of hydrobromide, citrate, malate, maleate, mesylate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, napthalene-2-sulfonate, ascorbate, oxalate, napthalene-1,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentisate, 1-hydroxy-2-napthoate, dichloroacetate, cyclamate, and ethane-1,2-disulfonate salts, of Compound 1.
Also note as implied by the language of instant claim 47, the composition of instant composition does include Oliver’s citrate salt.
The salt forming moiety of Compound 1 is shown below in partial structure
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With two nitrogens for protonation in the imidazole and three acidic groups in citric acid, one of skill in the art would expect salts containing different stoichiometric amount (molar ratio) of citrates (hemi-, mono- and di- citrate) can be made for optimization of physical and chemical properties. More specifically, it is well-known that citric acid and its salts are extensively used in pharmacology to optimize the stability, solubility, and bioavailability of therapeutic drugs. For example, Schunk similarly teaches different salts of basic active ingredients and further prefers citrate and hemicitrate (see column 6 line 56). Similarly, Gant teaches similar salts with different molar ratio of basic compounds and mono and dibasic acids including hemi-citrate salts. Further Kojima titled ‘Physicochemical properties of tamoxifen hemicitrate sesquihydrate’ teaches how to make citrate and hemi-citrate
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The compounds of Grant and Kojima are pure compounds as ascertained by X-ray crystal structures. Crystallization is routine in the art as part of isolating compounds in pure form. Olivier compounds are X-ray quality having been crystallized and therefore pure. It would have been obvious to one with skill in the art to isolate and purify similar salt forms of a similar formula such as a hemi-citrate salt when utilizing salts which may undergo multiple protonations. Olivier at column 8, first full paragraph teaches that the nature of the salt is not critical provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. In a salt, proton transfer occurs between Compound 1 free base and an organic acid or an inorganic acid. However, in some cases proton transfer is incomplete. In such cases, Compound 1 and the “co-former” molecules in the solid (i.e., “co-crystal”) interact through non-ionic forces such as hydrogen bonding.
The intended use of claimed composition and that of Oliver’s composition are the same.
There is common ground that the biological activity of a compound depends primarily on
its molecular structure. To reach its target it will at some point be in solution, e.g. in body fluids, where all differences among polymorphs disappear. The skilled person would thus expect that all polymorphs of the compound display the same pharmacodynamic profile. In addition, the methods to screen for polymorphs are well known in the art as taught by Morissette and Rodriguez. For example, according to Morissette (opening statement) “Active pharmaceutical ingredients can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, co-crystals and amorphous solids. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability and other performance characteristics of the drug”.
As noted the composition of Oliver and the instant have the same utility. According to MPEP 2144.04 [R-07.2022] Pure materials are novel vis-à-vis less pure or impure materials because there is a difference between pure and impure materials. Therefore, the issue is whether claims to a pure material are nonobvious over the prior art. In re Bergstrom, 427 F.2d 1394, 166 USPQ 256 (CCPA 1970). Purer forms of known products may be patentable, but the mere purity of a product, by itself, does not render the product nonobvious. Factors to be considered in determining whether a purified form of an old product is obvious over the prior art include whether the claimed chemical compound or composition has the same utility as closely related materials in the prior art, and whether the prior art suggests the particular form or structure of the claimed material or suitable methods of obtaining that form or structure. In re Cofer, 354 F.2d 664, 148 USPQ 268 (CCPA 1966).
The skilled person being investigating the therapeutic application of the Compound 1 (of Oliver) would thus routinely screen for different salts and polymorphs thereof to arrive at pure hemi-citrate salt. If such routine work yields other polymorphs, e.g. the presently claimed ones, then their provision is an obvious.
In the absence of any substantiated unexpected property for secondary considerations, the combined teachings of the above cited art, renders the claims unobvious.
As such the position taken is that there is extensive overlap in the conflicting claims.
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 1-65 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.
Amendments to claims are noted. The term ‘at least’ is does not define an upper limit of purity. As per disclosure at [116] many embodiments are indicated.
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However, the phrase is not defined by the claim, the specification (see above) does not provide a clear and limiting standard for ascertaining the requisite degree of purity envisioned, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention, rendering the claim indefinite.
Further the open-ended ‘comprising’ language renders the scope of the claims unclear. For the example what does 5% of the impurity entails. What are the impurities?
Dependent claims limitations further is confusing. For example, as defined the compound of formula 1 of base claim 46 has only one citric acid. As such it is unclear what compound the species of claim 48 composed of. It is unclear whether the mono here refers to base (imidazole).
Similarly, the hydrate of claim 49 is the same hydrate of 51 (which is recited as sesquihydrate). As such claim 46 is interpreted as being drawn to any number of embodiments containing different amounts of water (presumably depending on the humidity). This raises additional issues with respect to dependent claims 52-54, because it is unclear whether the diffraction pattern is drawn to, for example, a mono-hydrate or dihydrate or sesquihydrate hydrate.
Also, it is unclear if there is a separate crystalline Form I that is distinct from Form IA and Form IB (and other forms?). Is Form I a non-hydrated crystalline form? Or is “Form I” a general term used to describe all crystalline forms of the hemi-citrate salt, hydrated or not? Or are there no non-hydrated forms of the crystalline hemi citrate salt?
Due to the above issues, which render the cited claims indefinite as presently recited, the examiner cannot ascertain the metes and bounds of the claimed scope.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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