DETAILED ACTION
Claims 87-150 are pending and under consideration on the merits.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/16/26 was filed prior to the mailing date of a first Action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, it was considered by the Examiner.
Status of the Rejections
The 112(b) rejections are withdrawn in view of the amendment.
The 103 rejection of claims 124-128 is withdrawn in view of Applicant’s arguments and maintained as to the remaining claims, and expanded to include the newly added claims.
Notice of Allowable Subject Matter
Claims 124-128 are free of the prior art. These claims are limited to specific ingredients and specific amounts of the ingredients including microcrystalline cellulose as the plastic diluent and lactose monohydrate as the brittle diluent that result in weight ratios which the present specification shows enable higher drug loading while maintaining flowability, while going against the conventional procedure for increasing drug loading as argued by Applicants in their remarks, and the prior art does not teach or suggest the desirability of using the claimed ratios of these ingredients.
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.
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 87-123 and 129-150 are rejected under 35 U.S.C. 103 as unpatentable over Henary et al. (US Pat. Pub. 2020/0360374; published 11.19.2020) in view of Koziara et al. (US Pat. Pub. 2018/0177734; published 6.28.2018).
As to claims 87-123 and 129-150, Henary discloses a formulation comprising “Compound A” aka ”AMG 510” (synonymous with “sotorasib” of the present claims) and a method of treating cancer by administration of a therapeutically effective amount of the formulation to a subject in need thereof (claim 138)(paragraph 30). Henary discloses administering the sotorasib in a daily dose of 180, 360, 720, or 960 mg (see claim 1 of Henary), and teaches that a suitable dose may be calculated according to body weight, body surface areas, or organ size, and that determining the appropriate dose is routinely done by those of ordinary skill in the art without requiring undue experimentation (paragraph 38). Henary further teaches that the formulation may comprise a diluent such as a cellulose (paragraph 38), excipients such as starch or lactose (paragraph 52), a disintegrant, and a lubricant (paragraph 40), and also an excipient coating (paragraph 40).
Regarding claims 90-97 and 118-123, the formulation may comprise from about 1 to about 90 wt% sotorasib, which encompasses the ranges and amounts recited by these claims (paragraph 42).
As to claims 139-144, Henary further teaches that the cancer may comprise a mutated KRAS G12C cancer, and may be non-small cell lung cancer, colorectal, or pancreatic (paragraph 7).
Regarding claims 145-147 and 149, Henary teaches dispersing or dissolving the sotorasib dosage units in water immediately prior to administration (claims 145 and 149)(paragraph 43). Henary does not disclose heating or carbonating the water, which is therefore viewed as being non-carbonated (claim 146) and at room temperature (claim 147).
As to claims 87-123 and 129-150, Henary does not further expressly disclose that the diluent, disintegrant, and lubricant are present in amounts within the ranges or amounts of claims 87, 108, 112, or 118-123, that the lactose diluent is lactose monohydrate or that the cellulose diluent is microcrystalline cellulose as recited by claims 98-106, that the disintegrant is croscarmellose sodium or sodium starch glycolate (claims 109-111, 112-123), that the lubricant is magnesium stearate (claims 113-114), or that the sotorasib is present in the amounts recited by claims 115-117. Nor does Henary expressly teach the presence of a plastic diluent such as microcrystalline cellulose and a brittle diluent such as lactose monohydrate in combination as recited by claims 87-88, wherein a first ratio by weight of the plastic diluent to brittle diluent is within the range of claims 87-88 and a second ratio of the plastic diluent to sotorasib and the brittle diluent together is within the ranges of claims 87-88, nor of the plastic diluent to sotorasib weight ratio of claim 89, and wherein the brittle and plastic diluents have average Heckel yield pressures within the ranges of claim 107. Nor does Henary expressly teach the sotorasib dissolves within the parameters of claims 135-137, or that the tablet is coated with a coating composition comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and/or a coloring agent as recited by claims 129-134. Nor does Henary expressly teach a method of administration wherein the water has a volume of 120 mL (claim 148). Additionally, while Henary teaches that the composition may be administered in the form of a liquid or a solid (paragraphs 42-43), Henary does not expressly teach administering the composition in liquid form to a patient that has difficulty swallowing solids (claim 150).
Koziara discloses pharmaceutical tablet compositions comprising active ingredients along with excipients (paragraphs 4-5) such as 250mg or less of diluents/fillers such as microcrystalline cellulose, lactose monohydrate, or starches (claims 87 and 98-106), 0.5-5 wt% of lubricants of claims 87 and 113-114 such as magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, or talc (which encompasses the lubricant ranges of claims 87, 112, 118-124 and 126) and disintegrants such as croscarmellose or sodium starch glycolate of claims 87 and 108-111 (paragraphs 58, 60, 61, 62). Paragraph 74 discloses a specific embodiment of a tablet comprising lactose monohydrate (“brittle diluent” of the present claims”) and microcrystalline cellulose (“plastic diluent” of the present claims) as diluents in a total amount of 28.8 wt%, 1.3 wt% magnesium stearate as lubricant, and 6.2 wt% croscarmellose sodium as disintegrant, which results in a ratio of the plastic diluent to brittle diluent of about 4:1, which is within the ranges of claims 87-88. Regarding claims 129-134, the tablet is coated with a coating composition comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and indigo carmine (a “coloring agent”)(paragraph 74). Koziara teaches that in certain embodiments the tablet releases at least 80% or at least 90% of the active contained therein within 20 minutes measured using USP apparatus II with 75 rpm paddle speed at 37 degrees Celsius, which is within the ranges of claims 135-136 (paragraph 54).
As to claims 87-123 and 129-150, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the sotorasib formulation of Henary by selecting microcrystalline cellulose as the diluent and optionally in combination with lactose monohydrate, along with croscarmellose sodium or sodium starch glycolate as the disintegrant, and magnesium stearate as the lubricant, because Henary expressly teaches that its formulation may comprise lactose and celluloses as excipients without specifying any particular lactoses and celluloses, and further may comprise lubricants and disintegrants without specifying any particular lubricants, disintegrants, and Koziara expressly teaches that lactose monohydrate and microcrystalline cellulose are suitable forms of lactose and cellulose for use as diluents in pharmaceutical formulations, and that magnesium stearate is a suitable lubricant and croscarmellose sodium is a suitable disintegrant for use in pharmaceutical formulations, and further discloses a specific formulation comprising lactose monohydrate, microcrystalline cellulose, magnesium stearate, and croscarmellose sodium in combination, such that the skilled artisan reasonably would have expected that this combination of diluent, lubricant, and disintegrant would be suitable for use in the Henary pharmaceutical formulation. Such a modification is merely the combination of known elements according to known methods to achieve predictable results, which is prima facie obvious. MPEP 2143.
It further would have been prima facie obvious to select amounts of the lactose monohydrate, microcrystalline cellulose, magnesium stearate, and croscarmellose sodium that are within the presently claimed ranges and which results in a weight ratio of plastic diluent to brittle diluent within the range of claim 87, because Koziara discloses a specific embodiment comprising the use of amounts of lactose monohydrate, microcrystalline cellulose that reads on said ratio and which further comprises amounts of magnesium stearate and croscarmellose sodium that are close to the presently claimed amounts such that it can reasonably be assumed will result in similar properties (see MPEP 2155.05 I), and further because Koziara discloses the functions of these ingredients as being diluent, lubricants, and disintegrants, respectively, such that the skilled artisan would recognize that the amounts of these ingredients will affect the degree to which they are able to impart diluent, lubricating, and disintegrating abilities to the formulation, such that said amounts are result effective variables for which the skilled artisan would have been motivated to engage in an optimization process to determine the most effective amounts. MPEP 2144.05 I and IIA. The Office further notes that although the amounts of microcrystalline cellulose and lactose monohydrate diluents exemplified by Koziara are significantly less than the presently claimed amounts, the Koziara embodiment discussed above comprises four actives (i.e., elvitegravis, emtricitabine, tenofovir alafenamide hemifumarate, and cobicstate) which will take up a larger portion of the tablet composition, thereby requiring the use of less diluent. The skilled artisan would have been motivated to select higher amounts of the diluents for the Henary composition as it comprises only a single active. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding the second ratio of plastic diluent to sotorasib and brittle diluent together as recited by claims 87-88 and the ratio of plastic diluent to sotorasib of claim 89, since Koziara exemplifies amounts of the plastic and brittle diluents that read on the first ratio of claim 87 as discussed above and Henary teaches amounts of the sotorasib that are similar to the amounts recited by the dependent claims, the combination of Henary and Koziara is viewed as rendering the second weight ratio of claims 87-88 as well as the ratio of claim 89 prima facie obvious. It would have been well within the purview of the skilled artisan in the art of pharmaceutical formulations to test varying ratios of a diluent that is more plastic (and therefore more deformable) and a diluent that is more brittle (and therefore less deformable), relative to each other and to the other ingredients, in order to optimize the properties of the tablet, for example to ensure the appropriate friability, tensile strength, and hardness of the tablet (properties which are discussed by Koziara, for example, at Figure 9 and paragraphs 55-56), and ensure that the tablet disintegrates at an appropriate time to release the active within the time periods taught by Koziara. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
As to claims 90-97, and 115-123, it further would have been prima facie obvious to select amounts of the sotorasib active that are recited by claims 115-117, i.e., 120, 240, or 320 mg, and which are within the ranges of claims 90-97 and 118-123, because Henary expressly teaches the use of amount of sotorasib of 180, 360, 720, or 960 mg which includes amounts that are similar to the claimed amounts, and because Henary expressly suggests altering the amount of sotorasib to match a desired dosage form for a given patient and teaches that doing so involves only routine work without undue experimentation to one of ordinary skill in the art, and further because sotorasib is the active ingredient such that the amount of the sotorasib is a result effective variable which will affect the therapeutic efficacy of the composition for which the skilled artisan would have been motivated to engage in an optimization process to determine the most effective amounts. MPEP 2144.05 I and IIA. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claims 129-134, it further would have been prima facie obvious to coat the Henary tablet formulation with a coating composition comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a coloring agent such as indigo carmine, because Henary expressly teaches the tablet may be coated without providing further details which would have motivated the skilled artisan to search the pharmaceutical tablet arts for disclosure of proper coating materials, which would have led to Koziara which teaches said ingredients as suitable for use as a coating over a pharmaceutical tablet comprising lactose monohydrate, microcrystalline cellulose, magnesium stearate, and croscarmellose sodium excipients, such that the skilled artisan reasonably would have expected that they could be used to form a coating over the Henary composition. Such a modification is merely the combination of known elements according to known methods to achieve predictable results, which is prima facie obvious. MPEP 2143.
The resulting formulation will possess the sotorasib release properties recited by claims 135-137 and an average Heckel yield pressure within the range of claim 107 because it comprises the same ingredients in the same amounts and a product cannot be separated from its properties. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima face case of either anticipated or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01. Additionally, Koziara discloses specific embodiments for its formulation wherein the actives are released in similar amounts within similar times periods to those recited by the claims, such that the skilled artisan would recognize that incorporating the excipients from the Koziara embodiment into the Henary formulation would result in release profiles within the scope of the claims. Additionally, discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 148, it further would have been prima facie obvious to select an amount of water that is within the recited range with a reasonable expectation of success, since the amount of water is a result effective variable that will affect the ability of the water to serve as a carrier for the ingredients therein including the sotorasib, which is the same function that the water is serving in the composition administered by the claim. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 150, it further would have been prima facie obvious to administer the composition in liquid form to a patient that has trouble swallowing solids, because Henary teaches that the composition may be administered either as a solid or as an aqueous liquid, and the skilled artisan would recognize through the use of common sense that in those patients for whom a solid dosage form is contraindicated, such as because of a difficulty in swallowing solids, a liquid dosage form would be preferable. The Supreme Court stated in KSR that fact finders should not be denied recourse to common sense (82 USPQ2d at 1397).
Response to Applicant’s Arguments
Applicant asserts that the rejection relies on impermissible hindsight reconstruction of the claimed amounts of diluent, disintegrant, and lubricant and that neither cited reference teaches the claimed second ratio of claim 87 or the ratio of claim 89. Applicant argues that conventional approaches to increasing drug load create processability challenges for sotorasib due to its high compressibility combined with very low compactability. Applicant argues that claim 87 is characterized by a particular relationship between the amounts of the plastic and optional brittle diluent and the sotorasib, which would not have been arrived at via routine optimization because Tables 39-40, Formulations 2 and 3, and paragraphs 172-174 show that compositions having the recited weight ratios enable higher drug loading while maintaining flowability which is a surprising result, while the comparative compositions formulated according to the conventional method of maintaining the plastic brittle ratio while increasing drug load, and which therefore do not have the ratios recited by the claims, show a worsening of flowability as expressed by higher Carr index values.
In response, and as discussed in the rejection, since Koziara exemplifies amounts of the plastic and brittle diluents that read on the first ratio of claim 87 as discussed above and Henary teaches amounts of the sotorasib that are similar to the amounts recited by the dependent claims, the combination of Henary and Koziara is viewed as rendering the second weight ratio of claims 87-88 as well as the ratio of claim 89 prima facie obvious. It would have been well within the purview of the skilled artisan in the art of pharmaceutical formulations to test varying ratios of a diluent that is more plastic (and therefore more deformable) and a diluent that is more brittle (and therefore less deformable), relative to each other and to the other ingredients, in order to optimize the properties of the tablet, for example to ensure the appropriate friability, tensile strength, and hardness of the tablet (properties which are discussed by Koziara, for example, at Figure 9 and paragraphs 55-56), and ensure that the tablet disintegrates at an appropriate time to release the active within the time periods taught by Koziara. Ddiscovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
While Applicant argues, however, for the existence of surprising properties of inventive compositions having the recited ratio, whether unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). MPEP 70602(d).
Here, the data shown in the specification is for compositions comprising microcrystalline cellulose (MCC) as plastic diluent and lactose DG as the brittle diluent. There does not appear to be any evidence of record, however, that the ability of the claimed ratios of plastic diluent to brittle diluent and of plastic diluent to sotorasib and brittle diluent together to enable higher drug loading while maintaining flowability is a general property that would apply to any plastic diluent in combination with any brittle diluent. Therefore, the disclosure of superior results is not commensurate in scope with the present claims.
Applicant also argues that Henary’s disclosure of doses are for a method of treatment and not for the amount of sotorasib in a particular tablet or other dosage unit, such that Henary cannot be relied on to supply the amount of sotorasib presently claimed nor provide the structural amount needed for the rejection’s analysis of the second weight ratio.
In response, this argument is not persuasive because the skilled artisan would have had a motivation to incorporate the daily dose of sotorasib into a single unit dose in order to simplify administration and therefore improve patient compliance.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/ Primary Examiner, Art Unit 1600
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