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
This application filed on 12/15/2023, is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/EP2022/067276, filed on 06/23/2022, which claims priority to European patent application 21181306.8, filed 06/24/2021, and of European patent application 22156069.1, filed 02/10/ 2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 12/15/2023 and 01/05/2026, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
Status of claims
The premilitary amendment filed on 11/08/2023, that amended claims 3-8, 10, and 12-17, is acknowledged.
Claims 1-17 are pending.
Claim interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. MPEP § 2111.01 (III). However, specific embodiments of the specification cannot be imported into the claims, particularly where the subject claim limitation is broader than the embodiment. MPEP § 2111.01(II).
Claim interpretation of crystal form A:
Claim 1 recites “A crystalline form of sotorasib (Form A) according to the chemical structure as depicted in Formula (A) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.4 ±0.2)°, (12.3 ±0.2)°, (16.6 ±0.2)° and (17.8 ±0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm. claims 2-5, further recite spectroscopic characterizations. Instant specification defines the crystal form A as:
“Crystalline Form A of sotorasib of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities. [page 6]. Figure 1: illustrates a representative PXRD of sotorasib Form A according to the present invention. [page 7].
The art teaches that compounds can exists in multiple crystalline forms, and the gold standard to distinguish these forms is through XRPD. The XRPD consider to be the fingerprint in determining and identifying the particular crystalline form. In view of the instant specification, the claimed crystalline form A is defined by XRPD peaks as shown in Figure 1, and in view of the art, crystalline form A is defined by Figure 1 and will be interpreted as the crystal form of Figure 1.
The claims are given their broadest reasonable interpretation in light of the specification. MPEP 2111. In particular, the reference to “Crystalline Form A” in the instant specification and in the claims is always associated with the language “characterized by” and “comprising” regarding spectroscopic information i.e., XRPD peaks. Consistent with MPEP 2111.03, the claims are construed as being open-ended to allowing additional elements (“comprising” (and characterized by) is inclusive or open-ended and does not exclude additional, unrecited elements or method steps). In this case, the claims are construed as allowing other spectroscopic information as well as other solid forms “characterized” by additional information. However, in view of the above interpretation, crystalline form A is not defined by the “open-ended” claims 1-6 and the recited XRPD peaks, instead, the crystalline form A is defined by Figure 1.
Claim interpretation of predetermined and effective amount:
Claims 8 and 9 recite “A pharmaceutical composition comprising a predetermined and/or effective amount of the crystalline form A”. The instant specification defines the terms “predetermined” and “effective amount” as:
“A predetermined amount" as used herein with regard to sotorasib Form A refers to the initial amount of sotorasib Form A used for the preparation of a pharmaceutical composition having a desired dosage strength of sotorasib. [page 6].
The term "effective amount" as used herein with regard to sotorasib Form A encompasses an amount of sotorasib Form A which causes the desired therapeutic and/or prophylactic effect. [page 7].
As such, the terms are interpreted consistent with the specification.
Abstract
The Abstract of the disclosure is objected to because the Abstract recites “the present disclosure relates to a crystalline form of sotorasib”. Applicant is reminded of the proper language and format for an abstract of the disclosure. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
§ 103 Rejection over Chaves in view of Barth and Morissette
Claims 1-15 are rejected under 35 U.S.C. 103 as being obvious over M. Chaves et al. (US PG PUB 2020/0369662A1, 11/26/2020, “Chaves” cited in the PTO-892) in view of B. Lanman et al. (Journal of Medicinal Chemistry, 2020, Vol 63/Issue 1, PP. 52-65, “Lanman” cited in the PTO-892), W. Barth et al. (US Patent No. 4,432,987A, 02/21/1984, “Barth”, cited in the PTO-892) and S. Morissette, et al. (Advanced Drug Delivery Reviews, Volume 56, Issue 3, 2004, Pages 275-300, “Morissette” cited in the PTO-892).
Chaves teaches crystalline forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl) pyrido[2,3d] pyrimidin-2(1H)-one, (Compound 1), pharmaceutical compositions, and methods of treating a disease mediated by KRAS G12C inhibition, [0007]. Chaves’s compound 1 is represented by the structure below:
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Compound 1 is referred to in the instant claims as sotorasib.
Chaves teaches that polymorphs of a molecule can be obtained by a number of methods known in the art including melt recrystallization, melt cooling, solvent recrystallization, etc., and polymorphs can be detected, identified, classified and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, etc. [0080].
Chaves teaches crystalline anhydrous form I, wherein the crystalline anhydrous form I is characterized by the powder X-ray diffraction pattern substantially as shown in FIG. 5, [0117], , wherein crystalline anhydrous form I having a differential scanning calorimetry thermogram comprising an endotherm with an onset of about 293°C, [0120], wherein the crystalline anhydrous form of embodiment 1 having a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25° C. to about 275° C, [0121].
Moreover, Chaves teaches crystalline anhydrous form II of compound 1 characterized by the powder X-ray diffraction pattern substantially as shown in FIG. 10, wherein the anhydrous form II is the M atropisomer, [[0157]-[0159]], wherein form II having a differential scanning calorimetry thermogram comprising an endotherm with an onset of about 193° C., and a thermogravimetric analysis thermogram comprising a weight loss of about 1% to about 1.8% when heated from about 25° C. to about 250° C. [[0162], [0163]]
Furthermore, Chaves teaches crystalline form III of compound 1 characterized by the powder X-ray diffraction pattern substantially as shown in FIG. 15, wherein the anhydrous form III is the M atropisomer. [[0180]-[0182]], wherein form III having a differential scanning calorimetry thermogram comprising an endotherm with an onset of about 194° C, and a thermogravimetric analysis thermogram comprising an approximate negligible weight loss when heated from about 25° C. to about 250° C. [[0185], [0186]].
Chaves teaches that the X-ray powder diffraction data was obtained using the Phillips X-ray automated powder diffractometer (X'Pert) that was equipped with a fixed slit and a real time multi strip (RTMS) detector, the radiation was CuKα (1.54 Å) and the voltage and current were 45 kV and 40 mA, respectively, the data were collected at room temperature from 3.0 to 40.0 degree 2-theta, step size was 0.0167 degrees, counting time was 15.240 seconds, and the stage was rotated at a revolution time of 1.0 second, [0322]. Chaves teaches that the x-ray wavelength is 1.54 Å, [0226]. The 1.54 Å is equivalent to 0.154 nm. Chaves teaches that Thermogravimetric analysis was performed on a TGA Discovery Series, TA Instruments, and samples were analyzed under nitrogen at heating rates of 10° C./min over a temperature range from 25° C. to 325° C. [0326]. Differential scanning calorimetry data was collected using standard DSC mode (Discovery Series, TA Instruments), heating rate of 10° C./min was employed over a temperature range from 25° C. to 350° C, and analysis was run under nitrogen and samples were loaded in aluminum pans [0327].
While Chaves teaches that compound 1 (sotorasib) form crystalline form I, II, and III, there is variation in the spectroscopic characterization between Chaves’s crystalline forms and the claimed crystalline form A of sotorasib.
Lanman teaches the effectiveness of AMG 510 (sotorasib) as KRASG12C inhibitor, binding pocket of AMG 510 at KRASG12C, and optimization studies that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. [Abstract]. Lanman teaches that from these studies, (R)-38 (AMG 510, sotorasib) emerged as the standout molecule, showing good activity in cellular assays (p-ERK IC50 = 68 nM), moderate permeability (PAB = 6 μcm/s), and crystalline form of sotorasib shows exceptional oral bioavailability of 22–40%. [Pg. 59, col. 1].
In the same art area, namely pharmaceutical preparations and their use in treating disease, Barth teaches the following:
“[c]rystalline 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 in manufacturing procedures and in formation and use of acceptable dosage forms such as solutions, suspensions, elixirs, tablets, capsules and various pharmaceutically elegant preparations required by the medical and pharmaceutical professions.” [Pg. 2, col. 1, ln. 60- col. 2, ln. 2].
Morissette teaches an automated high-throughput crystallization to form polymorphs, salts, co-crystals and solvate forms of pharmaceuticals [Title, abstract]. The prior art describes the successful application of the automated high-throughput technique to several known pharmaceuticals and details how thousands of crystallization conditions can be performed in parallel, computer analyzed and then used to produce the polymorphic forms of a given pharmaceutical [Page 296, para. 2].
At the time of invention, one of ordinary skill in the art would have been motivated to prepare crystalline forms of the Chaves’s sotorasib because Barth teaches that crystalline forms are preferred over non-crystalline forms; have superior stability; are preferred in formulation of dosage forms; and are advantageous in manufacturing procedures. [page 2, col. 1, ln. 60- col. 2, ln. 2], and Lanman teaches that (AMG 510, sotorasib) in crystalline form demonstrates exceptional oral bioavailability (22–40%). [Pg. 59, col. 1], and increase bioavailability coincided with increase solubility. [Pg. 58, col. 2].
One of ordinary skill in the art practicing the Chaves’s pharmaceutical compound 1 (sotorasib) would form a crystalline form in accordance with the specific teaching of Chaves. Utilizing the routine “High-throughput salt selection” taught by Morissette [Pg. 285-287] one of ordinary skill in the art would arrive at the claimed invention. Specifically, because Chaves teaches that compound 1 form crystalline forms, i.e., form I, II, and III. Thus, one of ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed invention.
In the instant case one of ordinary skill in the art would have a reasonable expectation of success in following the teaching of Chaves and utilizing the well-known and routine automated high-throughput screening described by Morissette arrive at the claimed invention because such acts are conventional and routine in the art. One of ordinary skill in the art would be expected to apply methods within their technical grasp (such as automated high-throughput screening) to improve that which is already known in the art. The Supreme Court stated in KSR “if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person's skill.” KSR Intern. Co. v. Teleflex Inc., 127 S.Ct. 1727, 1731 (2007). Here, the use of an automated system to screen a pharmaceutical salt for crystallization is well known and specifically taught by Morissette. Therefore, the method is within the technical grasp of those of ordinary skill in the art and it would be obvious to one of ordinary skill in the art to use the same method and apply it to the Chaves’s compound, sotorasib.
Regarding the spectroscopic characterization of the obvious product, such properties are inherent in the product (MPEP 2112.02: "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). 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. Id.). In this case, one of ordinary skill in the art would have reasonably considered producing the crystalline salt form which would inherently show the same spectroscopic parameters as are in the claim. "[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, or ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).
Thus, claims 1-5 are rejected as prima facie obvious.
With regard to claim 6, Chaves teaches that wherein the anhydrous form I is the M atropisomer, [[0116], [0065]]:
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With regard to claims 7-12, Chaves teaches a pharmaceutical composition comprising the crystalline anhydrous form I, and a pharmaceutically acceptable excipient, [0127], wherein the pharmaceutical composition is a dosage form for oral administration, [0243], wherein the dosage form is a solid dosage form, [0244], wherein the solid dosage form is a tablet [0245], wherein the anhydrous crystalline forms are administered to a patient at dosages of 120 mg, 360 mg, 720 mg or 920 mg. [0105], wherein the pharmaceutical composition is prepared as a medicament for treating cancer having a KRAS G12C mutation . [0090], [ 0247].
With regard to claims 13-15, Chaves teaches a method of treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous form I, [0133], wherein said disease mediated by KRAS G12C inhibition is cancer, [0135], wherein the cancer having a KRAS G12C mutation, [0248], wherein the cancer having a KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer, [0249] wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, [0250].
§ 103 Rejection over Chaves in view of Barth and Morissette further, in view of Berkeley
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being obvious over M. Chaves et al. (US PG PUB 2020/0369662A1, 11/26/2020, “Chaves” cited in the PTO-892) in view of B. Lanman et al. (Journal of Medicinal Chemistry, 2020, Vol 63/Issue 1, PP. 52-65, “Lanman” cited in the PTO-892), W. Barth et al. (US Patent No. 4,432,987A, 02/21/1984, “Barth”, cited in the PTO-892) and S. Morissette, et al. Advanced Drug Delivery Reviews, Volume 56, Issue 3, 2004, Pages 275-300, “Morissette” cited in the PTO-892) as applied above to claims 1-15, further, in view of W. Berkeley et al. (Green Chemistry Letters and Reviews 2009, Vol. 2, No. 4, PP. 193-211, “Berkeley” cited in the PTOP-892).
The disclosures set forth above in the 103 Rejection over the same Chaves, Lanman, Barth and Morissette references are herein incorporated by reference. Relevant teachings of Chaves are discussed below.
Chaves teaches crystallization techniques including anti-solvent precipitation wherein solutions of compound 1 (sotorasib) were prepared in various solvents and an anti-solvent was then added, and the solids that formed were isolated and analyzed [0312]. Alternatively, solutions of sotorasib were prepared in various solvents, an anti-solvent was then added and the samples were allowed to evaporate, and the solids that formed were isolated and analyzed [0313]. Chaves teaches another crystallization technique, wherein saturated solutions of sotorasib were prepared in various solvents at either ambient or elevated temperature. The solids that formed were isolated and analyzed [0316]. Moreover, Chaves teaches that solutions of sotorasib were prepared in various solvents, and after complete dissolution was observed, the solvent was evaporated by vacuum at ambient or heated temperature, and the solids that formed were isolated and analyzed [0317], or the solution was allowed to evaporate at ambient in a partially covered vial, with or without a blanket of nitrogen gas, and the solids that formed were isolated and analyzed [0318].
Chaves teaches a method for preparing the crystalline anhydrous form II comprising combining an amorphous form of compound 1 (sotorasib) and methanol to form a crystalline anhydrous form II of sotorasib [0173], [0174]. Chaves teaches a method for preparing the crystalline anhydrous form I comprising combining form II of sotorasib and a suitable solvent, and removing the solvent to form a crystalline anhydrous form I of sotorasib. [0131]. Chaves teaches example of preparing sotorasib crystalline form I by charging 1.5 g of crystalline anhydrous Form II of sotorasib with 10 mL of water to form a slurry. The slurry was heated to 90° C. for 2h, then stirred overnight at RT. The solids were filtered, dried under vacuum and identified as crystalline anhydrous Form I by XRPD, DSC and TGA [0347].
In view of the above teaches, Chaves teaches the steps of:
dissolving sotorasib/sotorasib amorphous in a solvent (methanol);
crystallizing sotorasib anhydrous forms;
filtering (separating) the crystalline forms obtained; and
drying the crystalline forms obtained.
However, Chaves’s preparation method differs from claim 16 method in that the solvent is not iso-butanol. Chaves’s preparation method differs from claim 17 in that while Chaves includes dissolving in methanol and adding anti-solvent [0312,0313], Chaves does not teach that the anti-solvent is iso-butanol.
However, Berkeley provides one of ordinary skill with the motivation to select butanol as the solvent or anti-solvent for crystallizing sotorasib anhydrous crystalline form.
Berkeley teaches that manufacturing of active pharmaceutical ingredients (API) is associates with significant amount of waste by-product and pollutants, with 80% of the waste is solvent-related. [Pg. 193, col. 1, last para. -col. 2, 1st para.]. Berkeley teaches that solvents often influence the crystal form of the API, which directly determines dissolution rates, formulation, and bioavailability. Berkeley teaches that “the utilization of solvents also brings the disadvantage of solvent incorporation into the API, and if they cannot be removed, the amount must be controlled or limited to levels that are safe to the patient.” [Pg. 193, col. 2, last para.]. Berkeley teaches that the Center for Drug Evaluation and Research (CDER) of the USA Food and Drug Administration (FDA) lists four classes of solvents organized by patient safety and environmental considerations, wherein butanol listed as one of the most useful green solvents used in the pharmaceutical industry. Berkeley teaches that butanol is one of the solvents recognized as green selection, environmentally friendly solvents for manufacture, and selected as alternatives to traditional solvents. [Pg. 194, col. 1, 1st para. - col. 1, 1st para., Table 4]. Berkeley teaches that green solvents such as water and t-butanol had been introduced in place of ether and chlorinated solvents. [Pg. 195, col. 2, 3rd para.].
In view of the teachings of Berkeley, it would have been prima facie obvious to one of ordinary skill in the art looking to prepare Chaves crystalline forms to select butanol as the solvent/anti-solvent. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Berkeley teaches that selecting green solvent i.e., butanol decreases waste by-product and pollutants release form manufacturing of active pharmaceutical ingredients (API) by 80%; Berkeley teaches that Center for Drug Evaluation and Research (CDER) of the USA Food and Drug Administration (FDA) listed butanol as one of the most useful green solvent; Berkeley teaches that butanol is environmentally friendly solvent; selected as alternatives to traditional solvents; Berkeley teaches that t-butanol is as green as water; and Berkeley teaches that green solvent are useful in preparing crystal form of the API, which in hances dissolution rates, and bioavailability. Moreover, Chaves teaches methods of preparing the crystalline forms in detailed steps including dissolving in solvent, crystallizing, filtering, drying, isolating, and characterizing, and explicitly teaches “suitable solvent [0131], and in view of Berkeley’s teaching, one of ordinary skill would have been motivated to consider butanol a suitable solvent.
Berkeley teaches iso-butanol structure isomers, 1-butanol, and 2-butanol, [Pg. 195, Table 4], as one of the most useful green solvents. However, as discussed in 2144.09, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Thus, claims 16 and 17 are rejected as prima facie obvious.
Conclusion
Claims 1-17 are rejected. No claim is allowed.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622