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 .
Election/Restrictions
Applicant's election with traverse of Group I (i.e., claims 35-45 drawn to a room temperature stable ready to dilute injectable formulation comprising carfilzomib and one or more solvents where the formulation contains no more than 6% total impurities when stored for at least 3 months and when stored at 25°C and 60% relative humidity, and wherein the formulation does not contain any acidifying agent during the stability period of the formulation) in the reply filed on March 12, 2026, is acknowledged. Additionally, Applicant's election with traverse of Species A (i.e., a single and specific room temperature stable ready to dilute injectable formulation as one containing dimethylacetamide as the solvent, an antioxidant as an excipient, and three months storage duration at 25°C and 60% relative humidity as the storage conditions and total impurity) in the reply filed on March 12, 2026, is acknowledged.
The traversal is on the grounds that the cited Mohan reference (1) discloses storage at 2°C to 8°C in all examples whereas the instant invention achieves stability at room temperature (25°C) and 60% relative humidity and (2) requires an acidifying agent as a stabilizer during storage conditions whereas the instant invention achieves stability without an acidifying agent (See Applicant’s Response received on 3/12/26, pg. 10).
This is found persuasive because Mohan requires an acidifying agent in the carfilzomib formulation, which is now expressly excluded from the instant formulation. However, the groups and species still lack unity of invention in light of the combination of WO 2016/170489 A1 published on October 27, 2016 (cited in the IDS received 4/19/23) in view of WO 2011/116286 A2 published on September 22, 2011, and Nunes et al., Semin. Oncol. 44:377-380 (2017) as discussed in the 103(a) rejection below.
Also, please note that Species A is expanded to include propylene glycol and ethanol as solvents.
Status of Claims
Claims 1-34 were originally filed on October 14, 2022.
The amendment received on October 14, 2022, canceled claims 1-34; and added new claims 35-56. The amendment received on March 12, 2026, amended claims 35, 39, and 44-47.
Claims 35-56 are currently pending and claims 35-38 and 40-44 are under consideration as claims 46-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, and claims 39 and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 12, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/IB2021/053118 filed April 15, 2021, and claims priority under 119(a)-(d) to Indian Application Nos. 202021016383 filed on April 15, 2020; and 202021049395 filed November 12, 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Indian Application Nos. 202021016383 and 202021049395, which papers have been placed of record in the file. Please note that the Indian applications are in English and therefore no further action is necessary.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on January 24, 2023; and April 19, 2023 are being considered by the examiner.
Claim Objections
Claim 35 is objected to because of the following informalities: claim 35 recites, “…when stored for at least three months when stored at 25°C and 60% relative humidity; wherein the formulation…” It is respectfully requested that claim 35 recites, “…when stored for at least three months and when stored at 25°C and 60% relative humidity; and wherein the formulation…” in order to be grammatically correct. Appropriate correction is required.
Claim 35 is objected to because of the following informalities: claim 35 recites, “wherein the said formulation does not contain…” It is respectfully requested that claim 35 recites “the formulation” or “said formulation” as “the” and “said” are interchangeable, and thus, it is unnecessary to recite both words. Appropriate correction is required.
Claim 40 is objected to because of the following informalities: claim 40 recites, “…wherein the one or more solvents is selected from: ethanol, isopropyl alcohol, benzyl alcohol,…glycofurol, or mixtures thereof." It is respectfully requested that claim 40 recites, “…wherein the one or more solvents is selected from: ethanol, isopropyl alcohol, benzyl alcohol,…glycofurol, and mixtures thereof." Alternatively, Applicants can indicate a proper Markush claim as “…wherein the one or more solvents is comprising: ethanol, isopropyl alcohol, benzyl alcohol,…glycofurol, or mixtures thereof." See MPEP § 2173.05(h). Appropriate correction is required.
Claim 42 is objected to because of the following informalities: claim 42 recites, “…wherein the antioxidant is selected from: butylated hydroxytoluene, butylated hydroxy anisole, propyl gallate, and C.-tocopherol, DL-tocopherol, C-tocopherol acetate, C.-tocopherol Tocopherol Polyethylene Glycol…, ascorbic acid, sodium formaldehyde sulfoxylate,, or hydrophilic antioxidants, including sodium EDTA and thioglycerol." It is respectfully requested that claim 42 recites, “…wherein the antioxidant is selected from: butylated hydroxytoluene, butylated hydroxy anisole, propyl gallate, C-tocopherol, DL-tocopherol, C-tocopherol acetate, C-tocopherol Tocopherol Polyethylene Glycol…, ascorbic acid, and sodium formaldehyde sulfoxylate; or hydrophilic antioxidants including sodium EDTA or thioglycerol." See MPEP § 2173.05(h). Appropriate correction is required.
Please note the suggested amendment, removes the first recitation of “and” and inserted at the end of the Markush group, removed a “.” after “C” twice, inserted a semicolon instead of two commas at the end of the Markush to separate the two Markush groups, and replaced “and” with “or” since the second Markush group utilizes “including” instead of “selected from” as the transitional phrase. Also please note, the suggested amendment is presuming that claim 42 recites two Markush groups. If Applicant’s intention is to have one Markush group, the 112(b) rejection is applicable below.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 42 is directed to species of antioxidants including thioglycolic acid and ascorbic acid. Claim 42 is dependent upon claim 35 via claim 38. However, claim 35 requires that the formulation does not contain any acidifying agents. As such, it is unclear how the antioxidant can be an acid such as thioglycolic acid or ascorbic acid when the formulation cannot contain any acidifying agents. Thus, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to how the antioxidant can be an acidifying agent.
Please note that the Examiner is interpreting the scope of claim 42 such that the antioxidant is not either acid in order to advance prosecution. Also please note that claim 43 is rejected by virtue of its dependency.
Claims 42-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 42 is directed to species of antioxidants including C.-tocopherol and C-tocopherol acetate. However, it is unclear what structure is C.-tocopherol or C.-tocopherol acetate. There are only four forms of tocopherol; namely, α, β, δ, and γ (See Das Gupta et al., Mol. Nutr. Food Res. 60:1354-1363 (2016) at abstract). Thus, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to what structure is C.-tocopherol or C.-tocopherol acetate.
Please note that the Examiner is interpreting the scope of claim 42 such that the antioxidant is not either C.-tocopherol or C.-tocopherol acetate in order to advance prosecution. Also please note that claim 43 is rejected by virtue of its dependency.
Claims 42-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Pursuant to MPEP 2173.05(h), [a] Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. Here, claim 42 is directed to a Markush group of antioxidants selected from butylated hydroxytoluene,….sodium formaldehyde sulfoxylate,, or hydrophilic antioxidants, including sodium EDTA and thioglycerol. (emphasis added). Presuming each alternative recited in claim 42 is intended to be a species of the Markush group, the inclusion of “including” is open-ended thereby contradicting the scope of a Markush group, i.e., closed-ended. Since it is not readily apparent which hydrophilic antioxidants are encompassed, the scope of the Markush group encompasses unrecited species. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention because it is unclear what other alternatives are intended to be encompassed by each claim.
Please note that the Examiner is interpreting the scope of claim 42 such that the claim recites two Markush groups where the first one does not include hydrophilic antioxidants, but the second one is directed to hydrophilic antioxidants in order to advance prosecution. Also please note that claim 43 is rejected by virtue of its dependency.
Claim 43 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 43 recites the limitation "the total composition" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is noted that claim 43 is dependent upon claim 35 via claims 38 and 42. Claim 35 recites a “formulation”. Thus, recitation of “the total composition” is not supported.
The Examiner suggests for claim 43 to recite, “the total formulation”, in order to overcome the rejection.
Claim 44 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 44 is directed to where the formulation of claim 35 comprises carfilzomib or its pharmaceutically acceptable salts thereof and one or more solvents, wherein the formulation is stored at 25°C and 60% relative humidity or at 40°C and 75% relative humidity. However, claim 44 is dependent upon claim 35, which recites that the formulation contains no more than 6% total impurities when stored for at least three months and when stored at 25°C and 60% relative humidity…. Claim 35 requires a specific impurity percentage when stored at 25°C and 60% relative humidity, but claim 44 does not specify that the impurity percentage is distinct when stored at 40°C and 75% relative humidity. As such, it is unclear if the impurity percentage when the formulation is stored at 40°C and 75% relative humidity remains unchanged at no more than 6% total impurities. Therefore, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the presently claimed invention with respect to the impurity percentage when stored at a higher temperature and higher humidity level.
Please note that the Examiner is interpreting the scope of claim 44 such that the impurity percentage is the same as recited in claim 35 in order to advance prosecution.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 35-38 and 40-44 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/170489 A1 published on October 27, 2016 (cited in the IDS received 4/19/23) in view of WO 2011/116286 A2 published on September 22, 2011, and Nunes et al., Semin. Oncol. 44:377-380 (2017).
For claims 35, 38, and 40, with respect to a stable formulation comprising carfilzomib and one or more solvents where the one or more solvents is dimethylacetamide, ethanol, DMSO, propylene glycol, or polyethylene glycol and where the formulation contains an antioxidant:
‘489 teaches a stable, ready to use pharmaceutical composition comprising a proteasome inhibitor such as carfilzomib and at least one organic solvent where the organic solvent is selected from at least one protic solvent, at least aprotic solvent or mixtures thereof (See ‘489, pg. 5, 1st and last paragraph). The at least one aprotic solvent can be dimethylacetamide or dimethyl sulfoxide (See ‘489, pg. 6, 2nd paragraph). The at least protic solvent can be an alkyl alcohol such as methanol, ethanol, ethylene glycol, propylene glycol, or polyethylene glycol (See ‘489, pg. 6, 3rd paragraph). The inclusion of an antioxidant controls the oxygen content (See ‘489, pg. 7, 4th paragraph). Thus, ‘489’s pharmaceutical composition constitutes the instant stable formulation (note: the instant specification does not define a formulation that distinguishes it from a composition, and thus, ‘489 composition is interchangeable with a formulation) comprising carfilzomib and one or more solvents as recited in instant claim 35 where the one or more solvents can be at least one aprotic solvent such as dimethylacetamide or dimethyl sulfoxide and/or one or more protic solvent such as ethanol, ethylene glycol, propylene glycol, or polyethylene glycol as recited in instant claim 40, and where the formulation can further contain an antioxidant as recited in instant claim 38.
Regarding where the formulation does not contain an acidifying agent during the stability period of the formulation, ‘489 teaches that the compositions comprise organic solvents, buffers, solubilizers, pH modifiers, preservatives antioxidants, isotonicity adjusters and combination thereof (See ‘489, pg. 5, 4th paragraph). Although ‘489 teaches that a pH modifier, i.e., acidifying agent, can be included in the composition, ‘489 does not require a pH modifier in the stable, ready to use pharmaceutical composition. As such, a pH modifier is not a required compositional component at any period of the formulation. Thus, the teachings of ‘489 satisfy the claim limitation with respect to where the formulation does not contain any acidifying agent during the stability period of the formulation as recited in instant claim 35.
Regarding the composition being an injectable composition, ‘489 teaches that the compositions are suitable for parenteral administration and presented in a vial, ampoules or pre-filled syringe (See ‘489, pg. 5, 2nd paragraph). The compositions can then be administered via intravenous infusion (See ‘489, pg. 5, 2nd paragraph). Pursuant under MPEP 2111.02(II):
statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.); In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner)) and cases cited therein. (emphasis added).
As such, a formulation is intended to be administered via injection. Thus, the claimed formulation being an injectable formulation is the intended use of the formulation. Although ‘489 suggests administering the composition parenterally such as intravenously, the formulation being in the form suitable for parenteral administration renders the formulation capable of performing the claimed intended use, i.e., being injected as an injectable formulation. Thus, the teachings of ‘489 satisfy the claim limitations as recited in instant claim 35.
Regarding where the formulation is ready to dilute, as discussed supra, 489 teaches a stable, ready to use pharmaceutical composition comprising a proteasome inhibitor such as carfilzomib and at least one organic solvent where the organic solvent is selected from at least one protic solvent, at least aprotic solvent or mixtures thereof (See ‘489, pg. 5, 1st and last paragraph). ‘489 teaches that the composition is in liquid form and is ready to use and has a water content less than 2.5% w/w (See ‘489, pg. 4, 2nd paragraph). As such, ‘489 teaches that the composition can be prepared to be administered to patients without further reconstitution (See ‘489, pg. 4, 2nd paragraph). Although ‘489 does not expressly exclude that the composition can be further diluted, it does not expressly suggest where the composition can be combined with an infusion media (See instant, pg. 3, last paragraph).
‘286 teaches compositions comprising bortezomib where bortezomib has significantly increased stability of a prolonged period of time (See ‘286, [0009]). The compositions are substantially non-aqueous liquid formulations and/or formulations in which bortezomib is formulated with a hetero-bifunctional Lewis base donor compound to form a Lewis donor-acceptor complex (See ‘286, [0009]; claim 1). The liquid formulation that is substantially contains a substantially non-aqueous solvent system suitable for injection where the solvent system comprises propylene glycol as a main component (See ‘286, [0010], [0019]; claim 1). The solvent system can also contain a polar solvent such as ethanol, propylene glycol, DMSO, and dimethylacetamide (See ‘286, [0011], [0022]). ‘286 can also be in a lyophilized form instead of a solution (See ‘286, [0012]). When the composition is lyophilized, ‘286 teaches that the compositions will be administered after reconstitution with one or more pharmaceutically acceptable diluents such as saline, dextrose or water for injection, and optionally further contains an antioxidant, stabilizers, preservatives and/or co-solvents (See ‘286, [0014], [0016], [0018]). Most typically, the compositions are stable for months at ambient conditions (i.e., 25°C, 60% relative humidity) when stored in an amber vial with nitrogen head space (See ‘286, [0018]). As such, ‘286 teaches compositions comprising bortezomib in a stable liquid dosage form or as a stable lyophilized product such that degradation of bortezomib was maintained at or below 10% wt, and even below 2 wt% where the liquid formulation is stored over at least three months at ambient conditions (See ‘286, [0021], [0035]). Similarly, when bortezomib is in lyophilized form, the bortezomib is stable at ambient conditions for at least two months (See ‘286, [0021]). Thus, since ‘286 teaches stable lyophilized injectable compositions comprising bortezomib as a proteasome inhibitor that can be reconstituted prior to administration or the composition is in an aqueous liquid form, it would necessarily follow that ‘286 teaches a ready to dilute injectable formulation as instantly defined or as a ready to use injectable formulation, respectively.
Additionally, Nunes et al. teaches that bortezomib was approved in 2003 as a proteasome inhibitor to treat multiple myeloma and mantle cell lymphoma (See Nunes, abstract). Since that time, two additional proteasome inhibitors, carfilzomib and ixazomib have been approved (See Nunes, abstract). Thus, Nunes et al. demonstrates that both bortezomib and carfilzomib are proteasome inhibitors used to treat the same disease/condition.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of ‘489 and formulate a composition in a lyophilized form instead of a liquid form comprising carfilzomib as a proteasome inhibitor and a solvent system comprising at least one aprotic solvent such as dimethylacetamide or dimethyl sulfoxide and/or one or more protic solvent such as ethanol, ethylene glycol, propylene glycol, or polyethylene glycol without the presence of an acidifying agent where the lyophilized form can be reconstituted with one or more pharmaceutically acceptable diluents such as saline, dextrose or water for injection in order to administer the composition to a subject to treat multiple myeloma thereby constituting a ready to dilute injection formulation. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because a stable injectable lyophilized composition was known to contain bortezomib as a proteasome inhibitor, a solvent system containing a polar solvent such as ethanol, propylene glycol, DMSO, and dimethylacetamide that can be reconstituted prior to administration with one or more pharmaceutically acceptable diluents such as saline, dextrose or water for injection in order to administer the composition to a subject to treat multiple myeloma as taught by ‘286.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the stable injectable composition of ‘489 contains carfilzomib as a proteasome inhibitor, at least one organic solvent such as dimethylacetamide in a liquid form thereby constituting a ready to use formulation useful for treatment of multiple myeloma. Therefore, formulating the stable composition in a lyophilized form instead of a liquid form that is then reconstituted with one or more pharmaceutically acceptable diluents such as saline, dextrose or water for injection thereby constituting a ready to dilute formulation would support the treatment of multiple myeloma in a subject by constituting the simple substitution of one known element for another to obtain predictable results and/or Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding where the formulation is stable at room temperature and where the formulation contains no more than 6% total impurities for at least 3 months and when stored at 25°C and 60% relative humidity, ‘489 defines “stable” with respect to a composition as encompassing any characteristic of a composition which can be affected by storage conditions including individual impurity associated with carfilzomib or an excipient, total impurities, carfilzomib or excipient degradation products, water content, appearance, sterility, and color (See ‘489, pg. 8, 2nd paragraph). ‘489 also teaches that following storage of a composition at 25 +/- 2°C or 40 +/- °C for predetermined time period such as 1 week up to 36 months, the amount of any individual impurity present in the composition is not more than 3%, or in a range of 0.2% to 2.0% (See ‘489, pg. 8, last paragraph to pg. 9, 1st paragraph). Stability tests were performed at various conditions including long term storage (25°C/60% relative humility) (See ‘489, pg. 11, 1st paragraph) thereby suggestive of utilizing 60% relative humidity when the composition is stored long term at 25°C.
MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, as discussed supra, ‘489 teaches the claimed structural limitations of the instant formulation, i.e., carfilzomib and one or more solvents that is not an acidifying agent. Plus, ‘489 teaches that the formulations are stable at room temperature when stored for at least 3 months as recited in instant claim 35 where the formulation contains no more than 3% or 0.2% to 2.0% of any individual impurity.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ carfilzomib formulation differs, and if so to what extent, from the carfilzomib formulation taught in ‘489 with respect to the total impurity percentage instead of an individual impurity percentage when stored for at least 3 months and when stored at 25°C and 60% relative humidity. The cited art taken as a whole demonstrates a reasonable probability that the carfilzomib formulation of ‘489 is either identical or sufficiently similar to the claimed carfilzomib formulation with respect to the total impurity percentage that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Merely because a property of a carfilzomib formulation is not expressly taught in a reference does not make the known formulation patentable. The carfilzomib formulation possesses properties necessarily present which might not be displayed in the tests used in ‘489. Accordingly, the disclosure of ‘489 is a sufficient basis that the carfilzomib formulation contains no more than 6% total impurities when stored for at least three months and when stored at 25°C and 60% relative humidity.
In the alternative, even if the claimed carfilzomib formulation is not identical to the ‘489 carfilzomib formulation with regard to some unidentified properties, the differences between that which is taught and that which is claimed are considered to be so slight that the ‘489 carfilzomib formulation is likely to inherently possess the same properties of the claimed carfilzomib formulation particularly in view of the similar structural characteristics which they have been shown to share, i.e., carfilzomib, one or more solvents, and no acidifying agents. Thus, the claimed carfilzomib formulation containing no more than 6% total impurities when stored for at least three months and when stored at 25°C and 60% relative humidity would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Therefore, the teachings of ‘489 satisfy the claim limitation with respect to where the formulation is stable at room temperature and where the formulation contains no more than 6% total impurities for at least 3 months and when stored at 25°C and 60% relative humidity as recited in instant claim 35.
For claims 36-37, ‘489 teaches that the amount of carfilzomib in the pharmaceutical composition ranges from 100 to 1000 mg per 100 ml (i.e., 1 mg/ml to 10 mg/ml) (See ‘489, pg. 5, 3rd paragraph). Thus, the concentration of carfilzomib taught by ‘489 overlaps with the instantly claimed concentration ranges.
MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed concentration range of carfilzomib would have been obvious to one of ordinary skill in the art since the claimed range (i.e., about 10 mg/mL to about 100 mg/mL as recited in instant claim 36 and about 10 mg/ml to about 60 mg/ml as recited in instant claim 37) overlaps with the prior art concentration range of carfilzomib (i.e., 1 mg/ml to 10 mg/ml).
For claim 41, as discussed supra for claims 36-37, ‘489 teaches that the amount of carfilzomib in the pharmaceutical composition ranges from 100 to 1000 mg per 100 ml (i.e., 1 mg/ml to 10 mg/ml) (See ‘489, pg. 5, 3rd paragraph). Moreover, ‘489 teaches that the amount of protic and/or aprotic solvent in the compositions per 100 ml ranges from about 1-100 ml in any suitable ratio (See ‘489, pg. 6, 1st paragraph). Furthermore, ‘489 exemplifies 3 carfilzomib compositions where carfilzomib is present in an amount of 60 mg in each composition (See ‘489, pg. 9, example 1; pg. 10, example 2; and pg. 16, example 3). For example 1, the composition contains 10 ml propylene glycol and ethanol q.s. to 20 ml (i.e., at most 10 ml) (See ‘489, pg. 9, example 1). For example 2, the composition contains 5 ml and ethanol q.s. to 12 ml (i.e., at most 7 ml) (See ‘489, pg. 10, example 2). For example 3, the composition contains 2 ml propylene glycol, 0.6 ml dimethylacetamide, and ethanol q.s. to 6 ml (i.e., at most 3.4 ml) (See ‘489, pg. 16, example 3). When considering the density of propylene glycol is 1036 mg/ml, the weight of propylene glycol in each composition equates to 10,360 mg, 5180 mg, and 2072 mg, respectively. When considering the density of ethanol is 789 mg/ml, the weight of ethanol in each composition equates to at most 7,890 mg, 5,523 mg, and 2682 mg, respectively. When considering the density of dimethylacetamide is 937 mg/ml, the weight of dimethylacetamide equates to 562.2 mg. Since propylene glycol, ethanol, and dimethylacetamide are all solvents encompassed by claim 41, the ratio between carfilzomib and total solvent would be relative to the combined solvent amount in each composition. As such, the ratio (w/w) of solvent to carfilzomib in each composition would be 304.17:1 for example 1 (i.e., 10,360 mg + 7890 mg)/60 mg = 304.17), 178.38:1 for example 2 (i.e., (5180 mg + 5523 mg)/60 mg = 178.38), and 88.6:1 for example 3 (i.e., (2072 mg + 2682 mg +532.2 mg)/60 mg = 88.6). Thus, the (w/w) ratio range of solvent to carfilzomib is 304.14 to 88.6:1 thereby overlapping with the instant ratio range of 100:1 to 8:1. Individual solvent (w/w) ratio ranges similarly overlap and/or lie within the instant ratio range; for example, when the solvent is dimethylacetamide the ratio of dimethylacetamide to carfilzomib is 8.87:1. Although the ‘489 exemplified compositions contain an acidifying agent, which is excluded from the instant composition, when considering the teachings of ‘489 as a whole, the ‘489 compositions do not require an acidifying agent as discussed supra.
MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed (w/w) ratio range of solvent to carfilzomib would have been obvious to one of ordinary skill in the art since the claimed range (i.e., about 100:1 to about 8:1) overlaps with the prior art (w/w) ratio range of solvent to carfilzomib (i.e., 304.14 to 88.6:1; or 8.87:1 when utilizing dimethylacetamide as the sole solvent).
Additionally and/or alternatively, the (w/w) ratio of solvent to carfilzomib in the formulation is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal (w/w) ratio of solvent to carfilzomib in the formulation needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to adjust the (w/w) ratio of solvent to carfilzomib in light of the teachings of ‘489 as a whole for formulating a stable injectable formulation containing carfilzomib and one or more solvents such as propylene glycol, ethanol and/or dimethylacetamide without the inclusion of an acidifying agent, because an ordinary skilled artisan would have been able to utilize the teachings of ‘489 to obtain various (w/w) ratio parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the (w/w) ratio of solvent to carfilzomib in the formulation would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
For claims 42-43, as discussed supra for claim 38, ‘489 teaches that the carfilzomib composition includes an antioxidant. However, ‘489 does not specify the antioxidant recited in instant claim 42.
As discussed supra, ‘286 teaches stable injectable bortezomib compositions comprising a solvent system and a hetero-bifunctional Lewis base donor compound and further comprising an antioxidant. ‘286 teaches that the antioxidant can be butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, TPGS, or hydrophilic anti-oxidants such as EDTA and thioglycerol (See ‘286, [0032]). The concentration of the antioxidant will be between 0.005% and 5% w/w of the total composition (See ‘286, [0032]). Thus, the teachings of ‘286 suggest where the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, TPGS, or hydrophilic anti-oxidants such as EDTA and thioglycerol in a concentration from about 0.005% to about 5% w/w of the total composition as recited in instant claims 42-43.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of ‘489 and substitute butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, TPGS, or hydrophilic anti-oxidants such as EDTA and thioglycerol in a concentration from about 0.005% to about 5% w/w of the total composition as the antioxidant in a stable injectable formulation comprising carfilzomib and one or more solvents where the formulation contains no more than 6% total impurities when stored at 25°C and 60% relative humidity for at least 3 months without the presence of an acidifying agent. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because stable injectable compositions comprising bortezomib as a proteasome inhibitor, a solvent system and a hetero-bifunctional Lewis base donor compound were known to further comprise an antioxidant such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, TPGS, or hydrophilic anti-oxidants such as EDTA and thioglycerol in a concentration from about 0.005% to about 5% w/w of the total composition where the degradation of bortezomib was maintained at or below 10% wt, and even below 2 wt% where the liquid formulation is stored over at least three months at ambient conditions as taught by ‘286. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the stable injectable composition of ‘489 contains carfilzomib as a proteasome inhibitor, at least one organic solvent such as dimethylacetamide, and an antioxidant where the amount of any individual impurity present in the composition is not more than 3%, or in a range of 0.2% to 2.0% when stored at 25 +/- 2°C and 60% relative humidity for predetermined time period such as 1 week up to 36 months. Therefore, substituting butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, DL-tocopherol, TPGS, or hydrophilic anti-oxidants such as EDTA and thioglycerol in a concentration from about 0.005% to about 5% w/w of the total composition as the antioxidant would support the maintained stability of the carfilzomib composition by constituting the simple substitution of one known element for another to obtain predictable results and/or Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claim 44, as discussed supra, ‘489 teaches that the stable ready to use compositions have an amount of any individual impurity present in the composition is not more than 3%, or in a range of 0.2% to 2.0% when stored at 25 +/- 2°C or 40 +/- °C and 60% relative humidity for a predetermined time period such as 1 week up to 36 months (See ‘489, pg. 8, last paragraph to pg. 9, 1st paragraph; pg. 11, 1st paragraph).
Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed formulation is intended to be stored at 25°C and 60% relative humidity thereby constituting the intended use of the formulation, and thus, the question is whether the intended use imparts a structural limitation to the formulation. Since the intended use of storage at 25°C and 60% relative humidity does not impart a structural limitation, the “wherein” clause recited in instant claim 44 necessarily met. Therefore, the teachings of ‘489 satisfy the claim limitation as recited in instant claim 44.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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