DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 18 June 2025 has been entered. Applicants request for suspension of action under 37 CFR 1.103 filed concomitantly with the request for continued examination, previously granted, expired following three months from the date of the request.
Status of the Claims
Claims 1, 2, 6-15, 20, and 21 are pending, presented for examination and rejected as set forth below.
Claim Interpretation
The claims are directed to orally deliverable pharmaceutical compositions containing gemcitabine recited by dependent Claims 1, 10, 11, 14 and 15 (see 35 U.S.C. 112, fourth paragraph (indicating that “[a] claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers”)), water, a surfactant system selected from either polysorbate or oleoyl polyoxylglycerides, and carriers selected from either PEG, glycerol, or propylene glycol, where the identities and amounts of the solvent, surfactant(s) and carrier “self-microemulsify.” The examiner further notes that the language of the claims at present, describing a composition which “self-emulsify,” or which “forms an emulsion,” does not describe an emulsion, but merely that one must form an emulsion when combined with an aqueous medium. Therefore the language of Claim 2 directed to properties of emulsions formed and the physical characteristics thereof when the composition which is claimed is ultimately used, i.e., combined with an aqueous medium such as gastric juice or distilled water, or recitations of observed increases in bioavailability compared to the behavior of alternative compositions outside of the metes and bounds of the compositions claims amount to recitations of intended uses, rather than actual limitations, of the compositions claimed, and are of no consequence to the examination of the composition which is otherwise fully set forth. See Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003) (Particularly, an intended use will not limit the scope of the claim because it merely defines a context in which the invention may operate. Claim 10, 11, 14, and 15 further limit the identity of the solvent to ones which include water. Claims 6, 10, 11, 14, and 15 further limit the surfactants used. Claims 7, 8, 10, 11, 14, and 15 further limit the second hydrophilic carrier used. Claim 9 requires the composition possess a pH of greater than 4. Claim 12 requires the additional presence of D-alpha-tocopheryl-polyethylene glycol 1000 succinate. Claims 13-15 specify particular component concentrations. Claims 14, 1limit the compositions to ones consisting of the recited elements as were previously presented, with Claims 20 and 21 specifying that the compositions be incorporated into dosage forms, specifically a capsule.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 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.
Claims 1, 2, 6-15, 20, and 21 stand rejected under 35 U.S.C. 103(a) as being unpatentable over Chen (U.S. PGPub. 2003/0077297) in view of Gumkowski (U.S. PGPub. 2003/0022944), Talton (U.S. PGPub. 2009/0061011), and Yamashita (U.S. 6,919,372).
Chen describes orally deliverable formulations of pharmaceutical active agents. (Abs., [0045]). Chen indicates that the compositions according to the disclosure are designed to provide a significantly enhanced rate and extend of absorption and an subsequent substantial increase in the bioavailability of both hydrophilic and hydrophobic active agents, [0011; 0045; 0122; 0219], and that such formulations may contain both a solubilized portion and a solid portion [0012], but indicates that the solid particulate material need not be included in the vehicle retaining the solubilized portion of the active agent, thereby describing an emulsion free of solid particulates. [0225]. These suspensions are described by Chen, in multiple locations, as homogeneous suspensions. See, e.g., Chen [0263; 0336-37; 0347; 0361]. Chen indicates that hydrophilic as well as lipophilic active agents may be formulated according to the teachings provided, [0006; 0011], including anti-cancer agents such as gemcitabine, addressing limitations of Claims 1, 3, 4, 10, 11, 14, 15, 18 and 19. [0065]. Chen describes the vehicle component of the compositions as containing components selected from at least one of the following groups of components: hydrophilic surfactants, lipophilic surfactants, triglycerides, and solubilizers. [0045, 0119]. In particularly preferred embodiments, Chen teaches that the vehicle advantageously consists of combinations of multiple hydrophilic and lipophilic surfactants; nowhere in this explicit disclosure of a specifically preferred embodiments is the presence of a triglyceride, or indeed any oily or hydrophobic vehicle recited. [0204]. Chen indicates that the surfactants used can be either single surfactants or combinations of surfactants. [0122-127]. Among the disclosed surfactants Chen describes both LABRAFIL M1944CS PEG-6 apricot kernel oil corresponding to the oleoyl polyoxyglycerides, [0138 & Table 5] and TWEEN-80 corresponding to the polysorbate of instant Claims, including newly added Claim 19. [0151]. Chen additionally indicates that TPGS may advantageously be used as a surfactant in the formulations described, addressing the limitations of Claim 12. [0139]. Chen further describes a variety of solubilizers which may be used alone or in combination, which include the ethanol, propylene glycol, glycerol, polyethylene glycol set forth by the instant claims as either hydrophilic solvents or carriers, and isopropanol [0196], as well as water, specifically establishing that combinations of such solubilizers may also be employed, addressing the carrier and solvent limitations of Claims 1, 5-8, 10-12, 14, and 15. [0201]. Chen further describes including a variety of additional agents as “stabilizing agents,” including a broad recitation of excipients including buffers. [0273-74]. As Chen requires the inclusion of nothing excluded by the newly amended language describing the compositions as ones “consisting of” the elements recited, the newly added and amended claim language describing the compositions as ones “consisting of” remains an obvious modification of the teachings of Chen. See KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)) (indicating that “when 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.”). Chen indicates that these surfactant compositions, when contacted with an aqueous solution such as gastric contents or purified water, form an aqueous dispersion having a particle size of less than 1000nm, preferably less than about 200nm, addressing the limitations of Claim 2. [0208]. Chen indicates that each of the hydrophilic surfactant, lipophilic surfactant, triglycerides, and solubilizers, whether they be a single compound or a mixture thereof [0202], are advantageously each included in the composition in amounts ranging from between about 0.5-100% of the composition; because these ranges apply to each of the claimed surfactants, carriers and solubilizers, including carriers, the recited values overlap with those of the concentration ranges set forth the instant Claims, rendering them obvious. [0205]. Chen additionally indicates that between 20-95% of the active agent in the total dosage be solubilized in solution. [0216]. Chen discloses a number of exemplary compositions containing, for example fenofibrate in oily and aqueous carriers containing a variety of surfactants. [0345] These compositions are described as containing between 14-17% of the active agent, which overlaps the active agent limitations of the instant Claims. (Id.). To be sure, fenofibrate is a hydrophobic drug, however Chen does not distinguish between formulations of hydrophilic, amphiphilic, or hydrophobic drugs in formulating compositions according to the broader teachings of the disclosure. [0048]. Furthermore, as Chen clearly indicates that preferably the solutions described should contain between 20-95% of the total active agent as dissolved in solution [0216], the skilled artisan would recognize that the compositions of paragraph 345 would lead a skilled artisan to envisage compositions containing between 3-16% of an active agent solubilized in a liquid carrier. Chen indicates that in preferred embodiments, the composition is provided in a capsule form for oral administration, [0293], and may further be provided with a coating that resists degradation in the gastric environment for targeted delivery in the intestine. [0299-310].
Despite these teachings, including a description of the compositions as ones which, “upon mixing with an aqueous medium, the vehicle forms a clear aqueous dispersion”), (Chen, [0206-08], Chen does not specifically describe these compositions as ipsis verbis capable of self-emulsifying, nor does Chen describe buffering the composition to a particular pH.
Gumkowski teaches that orally deliverable compositions containing multiple surfactants, such as those disclosed as a particularly preferred embodiment of the vehicle described by Chen, are capable of, upon contact with an aqueous environment such as that described by Chen in paragraph 208, necessarily forming microemulsions by the natural action of the surfactants in the newly introduced aqueous medium. [0023, 0036]. Indeed, Gumkowski indicates that combinations of surfactants where one portion of the surfactant composition has a low HLB value and an additional portion has a high HLB value, are optimal for creating conditions in which a composition will self-emulsify, in that the surfactants will in essence emulsify themselves owing to the disparity in preferential solubility between the high and low HLB surfactants. [0040].
Neither Chen nor Gumkowski teach that such orally deliverable formulations should be made at a pH of greater than 4.
Talton indicates that oral delivery of pharmaceutical active agents is preferably provided at a neutral pH, by indicating that oral administration of a variety of active agents is preferred, but may present formulation problems as some drugs are insoluble at neutral pH. [0004]. This clearly conveys to the skilled artisan the desirability of providing oral formulations at a neutral pH, e.g. a pH of about 7, addressing the limitations of Claim 42.
Yamashita describes orally deliverable pharmaceutical dosage forms, including emulsions (Col.7, L.58-62), which may be pH adjusted if required. (Col.7, L.44-50). Albeit in the context of injectable compositions specifically, Yamashita teaches that sodium hydroxide may be used to adjust the pH of the compositions described. (Col.8, L.7-8). This would clearly suggest to the skilled artisan that compounds such as sodium hydroxide may be used generically to adjust the pH of orally deliverable, as well as injectable, compositions, such as emulsions.
It would have been prima facie obvious at the time of the instant application to have selected gemcitabine or a pharmaceutically acceptable salt thereof as the active agent and mixed it with combinations of oleoyl polyoxyglyceride, polysorbate, and TPGS as surfactants, and further combined such a mixture with solubilizers such as ethanol, propylene glycol, glycerol, polyethylene glycol and water, and encapsulated such a combination in an enteric capsule designed to release the drug in the intestine rather than the gastric environment from among the teachings of Chen, and adjust the pH to approximately neutral according to the teachings of Gumkowski, Talton, and Yamashita to arrive at the instantly claimed compositions described as self-emulsifiable. In addition, because each of the components recited as required by the Claims, specifically gemcitabine, water, glycerol, PEG, NaOH, polysorbate and oleoyl polyoxylglycerides and gemcitabine, water, propylene glycol, PEG, NaOH, polysorbate and oleoyl polyoxylglycerides are recited by Chen as modified above their combination is likewise an obvious modification of the prior art. Because the concentration ranges recited by the instant Claims are additionally within the ranges recited by Chen as advantageous in providing the compositions described, choosing a range within these broader ranges is likewise an obvious modification of the prior art. One having ordinary skill in the art would have been motivated to do so because Chen clearly teaches that combinations of surfactants including the oleoyl polyoxyglyceride, polysorbate, and TPGS claimed and solvents and carriers such as ethanol, propylene glycol, glycerol, polyethylene glycol and water are recognized as useful for solubilizing and effectively delivering orally deliverable compositions which, by the teachings of Gumkowski and Chen, would be recognized as self-emulsifying when contacted with an external aqueous medium such as the gastric environment. Furthermore, as Talton and Gumkowski advocate orally administrable compositions be formulated at or about neutral pH, and Yamashita clearly indicates that sodium hydroxide is among the alternative means of providing such an upward adjustment to the pH of such compositions, this modification too amounts to little more than the incorporation of a compound known to provide a desired property to a composition into which it has been incorporated. By the combined teachings of the above discussed references, the, the instant claims appear to amount to little more than an arrangement of art-known elements, each selected to provide the precise utility the art discloses they are suitable for providing, yielding nothing more than one would expect from such an arrangement; such a combination is obvious. KSR International Co. v. Teleflex, Inc., 82 USPQ2d 1385, 1395-97 (U.S. 2007).
Response to Arguments
Applicant's arguments filed 18 June 2025, which appear to represent a nearly verbatim reproduction of the arguments presented 5 February 2024, have been fully considered and unsurprisingly remain unpersuasive.
Applicants once more reassert the probative value of the declaration filed 20 August 2020 in an effort to establish secondary indicia of nonobviousness. Applicants arguments on this matter have been previously considered, multiple times in fact, and remain no more persuasive upon their continued repetition. As was set forth previously, while the scope of the compositions claimed had been narrowed, the probative value of the declaration failed for multiple additional reasons. First, nothing of record compares the composition claimed with the closest prior art. Second, nothing of the record demonstrates the compositions of the claims do anything other than what would expect to be seen by using the compositions of Chen in the manner set forth previously and again above. See In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”); see also In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)( “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.”), In re Skoner, 517 F.2d 947, 950 (CCPA 1975).
As applicants have repeatedly been reminded, the closest prior art to the instant claims available at the time of the instant application is the orally deliverable capsule formulation of gemcitabine HCl described by Veltkamp. See Veltkamp, et al, Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study, 14 Clin. Cancer Res. 3477, 3478 (June 1, 2008))(of record) (Indicating that “Gemcitabine (LY188011) was provided by Eli Lilly and Company as capsules containing gemcitabine as hydrochloride salt…”). Applicants comparison of bioavailability between the orally delivered formulations of the instant claims versus the bioavailability of i.v. formulations cannot serve to establish the nonobviousness of the instantly claimed orally delivered formulations as they fail to compare the invention to the closest prior art.
Once more, fatal to applicants position is the fact that Chen explicitly establishes that an improvement in bioavailability, of both hydrophobic and hydrophilic drugs, formulated according to the self-emulsifying drug delivery systems described is a result which is to be expected. See, e.g., Chen [0003; 0007; 0010-11; 0045; 0122; 0219]. Indeed, Chen describes an embodiment where the bioavailability of fenofibrate is approximately doubled when formulated as a self-emulsifying system. [0357].
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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