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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 February 2026 has been entered.
Status of the Claims
Claims 33, 37, 38, 40, 45-52, 54-65 are pending, presented for examination, and rejected as set forth below.
Claim Interpretation
Applicants claims are directed to a crystalline form of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4’-(morpholinomethyl)-[1,1’-biphenyl]-3-carboxamide hydrobromide, otherwise known as tazmetostat hydrobromide, in particles of defined sizes having an upper limit of particular levels of specified impurities. Dependent claims place further limitations on the particular size of the particles, or specify that the compound be a specific polymorphic form known as “Polymorph A.” Additional dependent claims indicate that the microparticles are to be provided in the form of pharmaceutical compositions, and in alternative dependent claims recite particular excipients which are to be combined with the tazmetostat particles, or indicate that the compound containing particles are free of any of a range of impurities or additional components. Newly added claims specify each of mean particle sizes (D50) and limitations on the particle sizes of the smallest ten percent (D10) of the particles present in the compositions.
Response to Amendment
The Declaration of Dr. Manoj Kakwani under 37 CFR 1.132 filed 17 February 2026 is insufficient to overcome the rejection of previously presented claims 33-57 based upon the combined teachings of Kuntz, Malakhov, and Keilhack as set forth in the last Office action because the data presented by Dr. Kakwani is not commensurate in scope with the invention claimed, and the evidence provided by Dr. Kakwani fails to establish either the unpredictability of the art or the inability of the skilled artisan to implement the guidance provided by the references of record to achieve the goals outlined by these references.
The Kakwani declaration, particularly the data presented relating to sections A-C, focuses on the process steps applicants allegedly had undertaken to arrive at the compositions being claimed. Once the examiner establishes a prima facie case of obviousness, the burden shifts to the applicant to rebut that case. In re Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). Applicants are reminded that the invention under examination is a composition of matter, not a process of manufacture, and as such fails to accurately reflect the invention being examined. See In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)( the evidence offered must be commensurate in scope with the invention claimed). As the data presented corresponding to sections A-C of the Declaration relate to an invention independent and distinct from that being claimed, these data and arguments in reliance thereon are unpersuasive.
Section D of the Kakwani declaration attempts to establish that the skilled artisan would not have been able to achieve the invention claimed, particularly the purity and particle size control, without undue experimentation, offering a single point of comparison between the process applicants assert lead to the compositions claimed, and a single process described by Kuntz. Applicants are reminded that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, Kuntz not only describes a specific procedure that can be utilized to obtain the crystalline polymorph A of tazmetostat claimed, but also guides the skilled artisan that a variety of recrystallization parameters may be utilized. See [0065-68]. Affidavits or declarations attacking the operability of a patent cited as a reference must rebut the presumption of operability by a preponderance of the evidence. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Further, since in a patent it is presumed that a process if used by one skilled in the art will produce the product or result described therein, such presumption is not overcome by a mere showing that it is possible to operate within the disclosure without obtaining the alleged product. In re Weber, 405 F.2d 1403, 160 USPQ 549 (CCPA 1969). "[A] prior art publication cited by an Examiner is presumptively enabling barring any showing to the contrary by a patent applicant." In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). Here, the Kakwani declaration simply demonstrates that an exemplary embodiment of the Kuntz reference results in a different composition from that which is obtained by a process applicants utilize. Applicants are reminded that art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Here, each of the ethanol and ethyl acetate applicants utilize in their recrystallization process are taught as possible solvent/cosolvent systems by Kuntz, as are heating and cooling steps required by the process described in the declaration for recrystallization processes. Utilizing a seed crystal to provide an initial nucleation point is also commonly employed in pharmaceutical crystallization processes. See, e.g. Hsien-Hsin Tung, Industrial Perspectives of Pharmaceutical Crystallization, 17 Org. Process Res. Dev. 445 (2013)). As such, nothing of either the realization of the objectives outlined by the teachings of Kuntz nor the particulars of the (unclaimed) process used to achieve the composition with the particle size and purity advocated by Kuntz and set forth by the instant claims appears beyond the capacity of a skilled artisan to achieve.
For at least these reasons, the Kakwani declaration is unpersuasive.
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 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 33, 37, 38, 40, 45-52, 54-65 are rejected under 35 U.S.C. 103 as being unpatentable over Kuntz (U.S. PGPub. 2015/0065503), in view of Malakhov (U.S. PGPub. 2009/0098207), Keilhack (U.S. PGPub. 2017/0360797), and Rao (Kallakurna Rao, Understanding the Relationship Between Process Parameters and Critical Quality Attributes of Tablets Produced by Batch and Continuous Granulation for a Low-Dose Caffeine Formulation Using Design of Experiments Approach, Doctoral Thesis, Rutgers University (May 2017)(available at: https://www.proquest.com/openview/55b21d266f0a206c179f3bc0a1bf96f0/1?pq-origsite=gscholar&cbl=18750)).
Kuntz describes as “Polymorph A” a particular form of the hydrobromide salt of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4’-(morpholinomethyl)-[1,1’-biphenyl]-3-carboxamide, shown below. [0037-38; 0040].
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“Polymorph A,” described by Kuntz, contains each of the degrees 2-theta recited by instant Claims 45 and 54, specifically about 17.5+/- 0.3 degrees and 22.0+/- 0.3 degrees. [0047]. Kuntz indicates that not only is the polymorph A to be substantially free of amorphous Compound I, but is to be present in amounts of at least 99% by weight of crystalline compound I hydrobromide. [0054]. Kuntz specifically advocates that the crystals of Polymorph A be “substantially free” of impurities, and more specifically the crystals of Polymorph A are described as containing less than 0.1% by weight of total impurities including but not limited to alternative polymorphs or residual solvents, water, or salts, defining a range overlapping, and therefore rendering obvious, the residual solvent levels recited by Claims 33, 41-44, 49, 53, and 55. [0053], See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). On the basis of this teaching, despite not specifying that the impurities to be absent are any of the residual ethanol, ethyl acetate, or toluene solvents, Kuntz addresses the limitations of Claims 33, 41-44, 49, 53, and 55 owing to the fact that the “less than 0.1% total impurities” defines not only a range encompassing the quantities of impurities recited by the claims, but also by suggesting the desirability of eliminating impurities including residual solvents from the crystals of polymorph A described therein. This teaching, combined with the fact that nothing of the Kuntz reference requires the presence of any of the ethanol, ethyl acetate, or toluene excluded from the claimed crystalline forms of tazmetostat hydrobromide polymorph A, suggests the limitations presently recited by the claims. Kuntz describes the crystals of Polymorph A as possessing different morphologies based on any of a variety of different recrystallization conditions. [0053]. Kuntz indicates that the particular crystalline forms of Compound I hydrobromide are particularly useful when formulated into solid dosage forms such as capsules, tablets, pulls, powders, and granules. [0076].
Despite teaching providing tazmetostat hydrobromide Polymorph A as a solid in pure crystalline form which can further be processed into pharmaceutical compositions, Kuntz does not specify the crystals of Polymorph A should be present in any particular range of sizes, nor does Kuntz teach incorporating such crystals into pharmaceutical compositions containing the excipients as recited by the instant Claims.
Malakhov describes microspheres of pharmaceutical agents. (Abs.). Malakhov indicates that for optimal efficacy, uniform formulations of pharmaceutical active agents are preferred. [0004]. Ideally, per the teachings of Malakhov, these microspheres are provided as uniform-sized microparticles containing high concentrations of the component so they remain stable and maintain their activity for long periods of time. [0008]. While employing language distinct from the particle population limitations of Claims 33, 37, 38, 40, 49, 50, 51, 52, and 58-61 concerning the D90, D50, and D10 percentage of particles having a particular size, and relative span falling within certain sizes, by describing the microparticle populations as “uniform,” the skilled artisan would recognize this encompasses populations where 100% of the particles possess these sizes, as that is the definition of the term “uniform.” With particles having uniform size, the requirements concerning the percentage of particles, D90, D50, D10 and relative span of particle sizes set forth by the claims is necessarily met. The Malakhov description of obtaining uniform microparticle sizes therefore addresses the limitations of Claims 33, 37, 38, 40, 49, 50, 51, 52, and 58-61, particularly when taken in consideration with the teachings of Rao, which indicates “[i]deally, one aims to achieve a distribution which would look like a narrow Gaussian distribution.” Rao, pg.20. This knowledge available to the skilled artisan establishes that each of the D90, D50, D10, and span are result-effective variables suitable for optimization via routine experimentation, rendering the D90 values of Claims 1, 37, 38, and 49-51, the span of Claims 40 and 52, the D50 of Claims 58 and 59, and the D10 of Claims 60 and 61 prima facie obvious in the absence of relevant secondary indicia of nonobviousness associated with these values. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.). Various recrystallization processes are recited by Malakhov as means of obtaining these pure homogeneously sized drug particles. [0010-16]. Malakhov indicates that a variety of active agents may suitably be provided as pure uniformly sized microparticles by these methods, including but not limited to chemotherapeutic or anti-tumor agents. See, e.g., [0018-19; 0029; 0035-37; 0041]. Malakhov indicates that the active component may suitably be present in these microparticles in amounts of about 99%, [0042], and more particularly describes embodiments where in excess of 99% of contaminants or components aside from the active have been removed, a range overlapping and therefore rendering obvious the limitations of Claims 33, 46, 49, 55, 63, and 65. [0074], See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). Malakhov indicates that the compound microparticles described have a size anywhere within the range of 0.001-50 microns, [0076], or more specifically having sizes of, for example, 5, 6, 15, 40, or 50 microns, addressing the limitations of Claims 33, 37, 38, 49-51, and 58-61. [0493], See Peterson, supra.
Keilhack describes as a cancer treating agent “Compound I,” and pharmaceutically acceptable salts, solvates, and polymorphs thereof, corresponding to the neutral form of tazmetostat, shown below. [0066; 0228].
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Keilhack describes pharmaceutical compositions containing these compounds which combine compound I with between 10-20% lactose monohydrate, about 11-19% low-substituted hydroxypropyl cellulose, about 3-7% sodium starch glycolate, about 1-10% hydroxypropyl cellulose, about 0.5-5% magnesium stearate, and about 1-10% of a coating composition, addressing limitations of Claims 48 and 57. [0113]. Solid dosage forms containing compound I are described as being formed from, for example, granules of the compound of formula I. E.g., [0125-132; 0151].
It would have been prima facie obvious to one having ordinary skill in the art to have chosen Polymorph A as the polymorphic salt of the compound of formula I for use in the compositions of Keilhack, because Keilhack explicitly indicates that salts and polymorphs of Compound I may be used in the formulations described, with Kuntz describing the exact polymorphic form of Compound I as suitable for inclusion in such pharmaceutical compositions. Malakhov and Rao advocates obtaining pharmaceutical crystals having the purity, particle sizes, and particle size distributions of the instant claims of among others chemotherapeutic or anti-tumor agents. Because the tazmetostat HBr Polymorph A of Kurtz is recognized as such a chemotherapeutic and anti-tumor pharmaceutical active agent suitably provided in crystalline form, substantially free from impurities including residual solvents, with total impurity concentrations recited as less than 0.1% of the crystalline compound for use in pharmaceutical compositions, the claimed combination of art known elements appears little more than the predictable use of prior art elements according to their established functions, and obvious thereby. See KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)) (indicating 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.”).
Response to Arguments
Applicant's arguments filed 17 February 2026 have been fully considered but they are not persuasive.
Applicants first (section i.) restate the limitations of the claims and asserts the art of record neither teaches nor suggests various aspects included in the claims. Not only is this incorrect, as the rejections made previously and again above establish, but it has long been held that such arguments are legally insufficient to properly raise an issue concerning the patentability of the invention claimed. In re Lovin, 652 F.3d 1349, 1357 (Fed. Cir. 2011) (“[T]he Board reasonably interpreted Rule 41.37 to require more substantive arguments in an appeal brief than a mere recitation of the claim elements and a naked assertion that the corresponding elements were not found in the prior art.”).
Applicants arguments presented in sections ii.-iv. simply reiterate the points raised by Dr. Kakwani in the declaration filed with the response on 17 February 2026. These issues have been addressed in greater detail above and will not be duplicated here.
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614