DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a continuation of US application 18/167,123 (now US 12,036,224) filed 10 February 2023 which is a continuation of 15/966,436 filed 30
April 2018. Acknowledgement is made of the Applicant's claim of domestic priority to provisional US applications 62/630,392 filed 14 February 2018, 62/514,246 filed 2 June 2017, and 62/491,655 filed 28 April 2017. The effective filing date of the instant claims is 28 April 2017.
Status of the Claims
• Claims 57-74 are pending.
• Claims 57-74 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 57-74 are rejected under 35 U.S.C. 103 as being unpatentable
over Venkatesan et al. (WO 2013/028818) in view of Markarian (https://www.pharmtech.com/view /using-micronization-reduce-api-particle-size) in view of lkeya et al. (US 2003/0055039) in view of Ashraf et al. (US 2011/0111018) in view of Tenengauzer et al. (US 6,764,997).
Venkatesan teaches compositions and methods for regulating JAK2 and Syk with a compound of Formula (I) (pg 2, Ins 23-25; below left) wherein one specific active agent is the active species of the instant claims (Ex 189, pg 110; below right). The active agent can be formulated as the hydrochloride salt (pg 25, lns 3-9).
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The therapeutic agent can be formulated using 0.0001-25% to be delivered by any route including oral, injection, inhalation, and others (pg 34, Ins 22-23; pg 35, Ins 19-21). For oral administration, the composition may be formulated as granules compressed into a tablet (pg 36, Ins 18-32). The granules can comprise any excipients including, but not limited to, antioxidants, binders, coatings, disintegrants, fillers, lubricants, granulating agents, and surfactants (pg 37, In 31-pg 38, In 12). The compositions of Venkatesan can be used to treat all types of inflammation, including
inflammation in skin or inflammation resulting from irritable bowel syndrome (pg 41, Ins
9-20, 25-26).
Venkatesan does not teach a formulation specifically comprising croscarmellose sodium and hydroxypropyl cellulose. Venkatesan also does not teach further including vitamin E, lactose monohydrate, or extragranular components.
Markarian teaches that micronization is used to reduce particles down to the micrometer or nanometer size in order to improve bioavailability of poorly soluble APls by increasing particle surface area and accelerating dissolution rates (pg 1). In one milling process, jet milling, a particle size in the 2-5 μm range is typical (pg 1).
lkeya teaches compositions for treating inflammatory diseases that may be tableted with various agents such as lactose (0.01-99%) [0082], magnesium stearate (lubricant; 0.01-99%) [0083], hydroxypropylcellulose and/or polyvinylpyrrolidone (aka crospovidone) (binder; 0.01-99%) [0084], croscarmellose sodium (disintegrant; 0.01-99%) [0085], sodium lauryl sulfate (suspending agent; 0.01-99%) [0088], a-tocopherol (Vitamin E, antioxidant; 0.01-99%) [0135], and microcrystalline cellulose (0.01-99%) [0135].
Ashraf teaches a tablet formulation comprising a kinase inhibitor (neratinib maleate) and further comprises microcrystalline cellulose (5-35%), croscarmellose sodium (0.5-8%), and povidone (granulation binder; 1-15%) as intragranular components [0041]. Lactose is an alternative filler to microcrystalline cellulose [0023]. The extragranular components include microcrystalline cellulose (4-25%), crospovidone (1-8%), and magnesium stearate (0.2-4%) [0041]. Croscarmellose is an alternative disintegrant to crospovidone [0024]. Ashraf further teaches the steps of preparing a tablet which includes, mixing the active agent and excipients, dissolving in a solvent and spray granulation, drying the granules, milling the granules, further adding extragranular components such as MCC and magnesium stearate, and compressing the blend into tablets [0042-0049].
Tenengauzer teaches methods of stabilizing azithromycin compositions comprising admixing the API with an antioxidant to improve resistance to degradation (abstract). Tenengauzer teaches that azithromycin is prone to degradation during storage due to the ability of the amine group to be oxidized (col 1, Ins 34-46). It is noted that azithromycin comprises two tertiary amine groups. The stabilizing antioxidant can be selected from the group that comprises vitamin E (col 3, Ins 7-22) and is present in 0.01-10% by weight of azithromycin (col 3, Ins 28-31 ). The vitamin E is admixed with the azithromycin before formulation into a dosage form (col 3, Ins 48-56). Additional excipients, binders, fillers, disintegrants, carriers, and the like are permitted in the composition (col 4, Ins 24-34).
It would have been prima facie obvious to the person of ordinary skill in the art to prepare an oral tablet for treating inflammation comprising granules of the active agent of Venkatesan as micronized granules. Said tablet would further comprise binders, fillers, disintegrants, surfactants, coatings, and antioxidants, which could have been selected based on the kinase inhibitor formulations of Ashraf and lkeya. Moreover, it would have been obvious to select vitamin E as the antioxidant because Tenengauzer teaches said agent as providing a stabilizing effect to azithromycin, an active agent with oxidizable amine groups. To be sure, the active species of the instant claims comprises multiple secondary and tertiary amine groups which would be subject to oxidation reactions. Therefore, the disclosure of Tenengauzer applies to the active because of the underlying mechanism of vitamin E stabilizing amine groups that can be oxidized. Therefore, there would have been a reasonable expectation of success that the resulting tablet formulation would be stable at 40 ºC and varying relative humidity, due to the stabilizing effect of the vitamin E. Since the active agent of Venkatesan is identical to that of the claims, thus there is a reasonable expectation based on the similarity in formulations between the instant claims and the prior art of an API degradation impurity level of about 0.6% after one week storage. It is noted that “products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (see MPEP 2112.01 (II)).
Regarding the specific selection of excipients in the dependent claims, the art is not specific and the instant claims do not provide evidence of any surprising or unexpected results based on a particular combination thereof. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is ... a person of ordinary creativity, not an automaton." Id. At 1742. Consistent with this reasoning, it would have been obvious to have selected various combinations of various tablet excipients from within a prior art disclosure, to arrive at compositions "yielding no more than one would expect from such an arrangement." As such, it would have been obvious to select any known pharmaceutically acceptable excipients to use in the composition of Venkatesan. Based on the teaches of lkeya and Ashraf, a composition comprising API, a-tocopherol (Vitamin E; 0.01-10%), lactose (0.01-99%), hydroxypropylcellulose (of any kind) (0.01-99%), crospovidone (0.01-99%), sodium croscarmellose (0.01-99%), microcrystalline cellulose (0.01-99%), sodium lauryl sulfate (0.01-99%), magnesium stearate (4-25%) would have been an obvious selection of commonly used excipients. Moreover, it would have been obvious to use said excipients in either the granules or the extragranular portion as is commonly known in the art. Although Venkatesan is not specific as to the milligram amount of active, the art does provide a broad range of from 0.0001-25% by weight. In a common 400 mg tablet, 5% active agent would comprise 20 mg and 20% would be 80 mg. The prior art teaches all the required excipients (lactose, croscarmellose sodium, vitamin E, lactose monohydrate, and hydroxypropyl cellulose) as being useful for the preparation of pharmaceutical tablets of compressed granules.
Ashraf is applied as a reference that teaches a common formulation in the art of kinase inhibitors as API in tablets. The ranges and locations (intragranular or extragranular) of agents generally match up with the desired amounts in the instant claims (aside from the inclusion of vitamin E). Generally, it is prima facie obvious to substitute one equivalent component or process for another, each of which is taught by the prior art to be useful for the same purpose (see MPEP 2144.06). Thus, the prior art knowledge would have given the skilled artisan guidance on how to formulate a stable formulation comprising a kinase inhibitor given the broad disclosure of Venkatesan. The amounts and location (intragranular or extragranular) of each excipient can be determined by the artisan based on the desired tablet properties. That being said and in lieu of objective evidence of unexpected results, the formulation amounts and locations of excipients can be viewed as variables which achieve the recognized result of successfully formulating a tablet of required shape and hardness. The optimum or workable range of each excipient can be accordingly characterized as routine optimization and experimentation (see MPEP 2144.05 (ll)B). "[Discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellants provide no evidence of any secondary consideration such as unexpected results that would render the optimized amounts of excipients as nonobvious.
Regarding the size of the micronized particles, it would have been obvious to mill
the particles to 2-5 μm as taught by Markarian. The resulting composition renders obvious instant claims 57-74.
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 57-74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,036,224 in view of Tenengauzer et al. (US 6,764,997).
Although the claims at issue are not identical, they are not patentably distinct from each other because although ‘224 recites all the components of the instant formulation, the ‘224 claims do not limit the stability of the formulation of the instant claims. Tenengauzer teaches methods of stabilizing azithromycin compositions comprising admixing the API with an antioxidant to improve resistance to degradation (abstract). Tenengauzer teaches that azithromycin is prone to degradation during storage due to the ability of the amine group to be oxidized (col 1, Ins 34-46). It is noted that azithromycin comprises two tertiary amine groups. The stabilizing antioxidant can be selected from the group that comprises vitamin E (col 3, Ins 7-22) and is present in 0.01-10% by weight of azithromycin (col 3, Ins 28-31 ). Thus, due to the inclusion of vitamin E in the ‘224 formulation, which is known to be a stabilizing antioxidant, the storage stability of the instant claims is obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW S ROSENTHAL whose telephone number is (571)272-6276. The examiner can normally be reached M-F 8-5pm EST.
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/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613