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 .
Status of the Claims
Claims 1-9 and 75 are pending.
Claim 4 is withdrawn from consideration as directed to non-elected inventions.
Claims 1-3 and 5-9 are presented for examination and rejected as set forth below.
Claim Interpretation
Applicants claims are directed to compositions which combine carfilzomib with a solvent selected from a Markush-type listing of alternatives which includes each of dimethyl sulfoxide and dimethylacetamide, a co-solvent system which includes, per applicants election, each of ethanol and polyethylene glycol, optionally combined with a first co-solubilizing agent, also containing a “second” co-solubilizing agent selected from PVP, mannitol, and glycine, which is provided as an aqueous solution having a pH between 2.5-4.5. These compositions are to be either a ready-to inject solution or a lyophilized powder or cake, and may be injected intravenously or subcutaneously. Applicants are reminded that a recitation of an intended use will not limit the scope of the claim because it merely defines a context in which the invention may operate. Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003). As such, the administration language of the composition of Claim 1 is not afforded patentable weight. Claim 2 narrows the identity of the first solvent, and Claim 3 the co-solvent to ethanol and polyethylene glycol, which in Claim 5 is narrowed to PEG400 and ethanol along with an acidic, ester, organic salt, organic base, or C1-4 alkyl alcohol. Claim 6 specifies the acid is to be a member of a Markush -type listing of alternatives, with Claim 7 specifying the inclusion of one of two organic salts. Claim 8 indicates that ethanol amine or isopropyl alcohol is to be present as a co-solubilizing agent, with Claim 9 reciting a variety of co-solvent systems including one where 75-92% of the composition is a 1:1 (by weight) combination of PEG400 and ethanol.
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 1-3 and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Shete (U.S. PGPub. 2018/0117054) in view of Chandrashekhar (WO2016/116882).
Shete describes single dose cyclodextrin-free ready-to-use formulations of carfilzomib of Claim 1 for direct introduction into an infusion bag or direct dilution for infusion solutions. [0015-18]. These solutions are described as containing anywhere from 0.5-20% carfilzomib. [0039]. Injectable formulations may contain any of a variety of pharmaceutically acceptable solvents and excipients including water, dextrose, Ringer’s, and isotonic saline solutions, as well as any of buffers, surfactants, or preservatives. [0034; 0046]. Each of the dimethyl sulfoxide, dimethylacetamide, ethanol, isopropyl alcohol and polyethylene glycol recited by Claims 1-3 and 8 are identified as suitable components of the non-aqueous water-miscible solvent systems for use in the ready-to-use formulations. [0042]. Acid stabilizers including each of the lactic and citric acids recited by Claim 6 are identified by Shete as usefully included in these formulations in concentrations from about 0.1-50% of the composition. [0044-45]. PEG400 of Claims 5 and 9 is identified as a particular polyethylene glycol which can be included in the composition in concentrations of between 10-90% of the composition. [0049]. Shete indicates that the compositions should have a pH within the range of about 3-6, overlapping and therefore rendering obvious the range of Claim 1. [053], 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.”). While no particular concentration limitations, or relative ratios of PEG400 to ethanol are required by Shete, it must be remembered that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. 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.). Here, Shete indicates that each of ethanol and PEG400 may be included in the injectable carfilzomib compositions described to serve as a water-miscible solvent and surfactant, respectively, to stabilize the carfilzomib for injection. As such, the skilled artisan would recognize each of these components as result-effective variables suitable for optimization through little more than routine experimentation, rendering the concentrations and ratios recited by Claim 9 prima facie obvious.
The specific combination of features claimed is disclosed within the broad teachings of the Shete reference, but such “picking and choosing” from among several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). Where, as here, the reference does not provide any motivation to select this specific combination of carfilzomib, dimethyl sulfoxide of Claim 2, ethanol and PEG400 in a 1:1 ratio present as between 75-92% of the composition of Claims 3, 5, and 9, combined with isopropyl alcohol of Claim 8 and lactic acid of Claim 6 with an aqueous component buffered to a pH of between 3-6 required by Claim 1, anticipation cannot be found.
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 prima facie obvious to have selected various combinations of carfilzomib, dimethyl sulfoxide, ethanol and PEG400 in a 1:1 ratio present as between 75-92% of the composition, isopropyl alcohol and lactic acid with an aqueous component buffered to a pH of between 3-6 as a ready-to-inject solution from within a prior art disclosure, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
Shete therefore suggests ready-to-inject compositions of carfilzomib, dimethyl sulfoxide, ethanol and PEG400 in a 1:1 ratio present as between 75-92% of the composition, isopropyl alcohol and lactic acid with an aqueous component buffered to a pH of between 3-6.
Shete does not, however, describe including any of the “second” co-solubilizing agents recited by amended Claim 1, nor the benzalkonium chloride of Claim 7 as a component of the compositions, even though the inclusion of pharmaceutically acceptable preservatives is described. [0046].
This is cured by the teachings of Chandrashekhar, which indicates that at the time the present application was filed, benzalkonium chloride was known to be useful as a pharmaceutically acceptable preservative in carfilzomib compositions. (Pg.6). In addition, Chandrashekhar had found that combining a sugar such as the instantly claimed mannitol or glycine with a suitable solvent and acidifying agents has been found to yield stable formulations that overcome the disadvantages associated with prior art carfilzomib solutions, with combinations of maleic and citric acid and mannitol specifically embodied. (Pg.7-8; 16)
It would have been prima facie obvious to have incorporated mannitol or glycine with the carfilzomib solutions of Shete and also to have used benzalkonium chloride as a pharmaceutically acceptable preservative in the carfilzomib compositions of Shete. This is because Shete indicates that pharmaceutically acceptable preservatives may be incorporated into such compositions, while Chandrashekhar indicates that benzalkonium chloride was just such a pharmaceutically acceptable preservative compatible with carfilzomib compositions, and the combining acids such as the claimed citric and maleic acids with sugars including the mannitol and glycine newly added to the claims has been associated with overcoming disadvantages of carfilzomib solutions known in the prior art. Applicants are reminded that generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). In addition, because the art motivates a skilled artisan to combine sugars such as mannitol or glycine with acids such as maleic or citric acid in carfilzomib to overcome drawbacks associated with alternative prior art carfilzomib compositions, the inclusion of either of these sugars in the compositions of Shete is prima facie obvious. See In re Sernaker, 702 F.2d 989, 994-95 (Fed. Cir. 1983) (“The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”)
Response to Arguments
Applicant’s arguments with respect to the objections to Claims 7 and 9 have been fully considered and are persuasive in view of the amendments applicants have submitted to these claims. The objection of the office action mailed 6 April 2026 has been WIHTDRAWN.
Applicant's arguments filed 6 July 2026 have been fully considered but they are not persuasive.
As a threshold matter, owing to applicants amendments to the claims, the previous rejection predicated on the teachings of Shete alone has been withdrawn, and the rejection based on the combined teachings of Shete and Chandrashekhar modified to address the newly required inclusion of a “second” co-solubilizing agent selected from the group consisting of polyvinylpyrrolidone, mannitol, and glycine.
Applicants assertion that Shete does not describe or suggest an aqueous solution buffered to a pH between 2.5-4.5 is inaccurate, as set forth above, for Shete indeed describes just such a composition. While Shete may describe embodiments free of water, the entirety of the Shete disclosure is not so limited. Applicants are reminded that all elements of each prior art reference need not read on the claimed invention, rather, the proper test for obviousness is what the combined teachings would have suggested to a person of ordinary skill in the art. In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). Because Shete also describes aqueous solutions of carfilzomib having a pH of between about 3-6, see Shete [0015; 0018-20; 0034; 0037-38] (indicating that “the term ‘ready-to-dilute’ refers to a formulation which can be directly combined with a diluent (e.g., dextrose solution, saline solution…[t]he term ‘ready-to-use’ refers to any preparation of carfilzomib which can be administered to patient [sic] directly without any further dilution or processing”), Applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
THIS ACTION IS MADE FINAL. 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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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