DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This is a National Stage application of PCT International Application
PCT/EP2022/080147, filed on October 27, 2022, which claims the benefit of European Patent Application EP21383207.4 filed on December 23 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/21/2024 has been considered by the examiner.
Status of Claims
Claims 1-8, 10-14, and 16-18 are pending and under examination. Claims 9, and 15 are canceled.
Specification
The abstract of the disclosure is objected to because the abstract does not adequately summarize the disclosure and it is unduly brief and fails to present a concise statement of the technical disclosure of the application as required by 37 CFR 1.72(b). The abstract is substantially below the preferred 50-150 words range and omits significant aspect of the disclosed subject matter. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 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 1-8, 10-14, and 16-18 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 1 recites “wherein said composition has not more than 18.5 ppm of N-nitroso-varenicline impurity (II)… with respect to varenicline.” However, the claim fails to specify the condition under which the recited impurity level is measured. For example, the claim does not specify whether the impurity limitation is determined immediately after manufacture, after storage, after accelerated stability testing, after exposure to elevated temperature and/or humidity conditions, under open or closed packaging conditions, and/or after any particular period of time.
The specification demonstrates that the impurity levels vary substantially depending upon the testing and storage conditions employed. For instance, the specification reports impurity measurements after manufacture, after storage for various durations, after stress testing at 40oC/70% RH and 70oC/75%RH, under open dish conditions, and under different blister packaging systems (e.g., PVC/Alu and Aclar/Alu). The reported impurity values vary significantly depending on these differing conditions.
Accordingly, because the claims fail to identify the relevant conditions and/or temporal point for determining whether the “not more than 18.5 ppm” limitation is satisfied, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed invention. As such, the scope of the claims is not reasonably certain.
Additionally, claims 3, 5, and 10 are indefinite because the terminology “preferably”, “more preferably”, and “particularly” renders the scope of the claims unclear. Specifically, it is unclear whether the recited preferred embodiments constitute affirmative claim limitations or merely optional descriptive language. Therefore, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed invention.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8, 10-14, and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to a broad genus of solid pharmaceutical compositions comprising varenicline or a pharmaceutically acceptable salt thereof, at least one scavenger agent of nitrite anion, and one or more pharmaceutically acceptable excipients or carriers, wherein the compositions contain not more than 18.5 ppm of N-nitroso-varenicline impurity of compound formula (II) with respect to varenicline.
However, the specification does not reasonably convey to one of ordinary skill in the art that Applicant had possession of the full scope of the claimed genus at the time of filing. In particular, the claims broadly encompass essential an “solid pharmaceutical composition” containing varenicline, scavenger agent(s), and excipient/carrier systems capable of satisfying the claimed impurity limitation. Nevertheless, the specification only discloses a limited number of working embodiments directed primarily to tablet formulations, utilizing specific excipient systems, specific scavenger agent, specific scavenger concentrations, and specific packaging/storage conditions.
For example, the working examples are limited to tablet compositions employing particular excipients such as microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Likewise, the examples utilize only limited scavenger systems, primarily ascorbic acid and ammonium chloride, under particular concentration ranges and testing conditions. The claims however, are not limited to tablets, the exemplified excipient systems, the exemplified scavenger concentrations, nor the exemplified storage or packaging conditions. Instead, the claims broadly encompass the entire genus of solid pharmaceutical compositions capable of achieving the recited impurity limitation of not more than 18.5 ppm.
The specification further demonstrates that impurity formation is highly dependent upon formulation variables and testing conditions, including but not limited to scavenger concentration, packaging configuration, humidity, temperature, and storage duration. Nevertheless, the specification does not provide sufficient representative species of other identifying characteristics demonstrating possession of the full scop0e of solid pharmaceutical compositions encompassed by the claims that would achieve the recited impurity limitation.
Accordingly, the specification fails to reasonably convey to one of ordinary skill in the art that Applicant had possessed the full scope of the presently claimed genus of solid pharmaceutical compositions characterized by the recited impurity limitation.
Claims 1-8, 10-14, and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a tablet composition employing particular excipients in specific amounts such as microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, and varenicline tartrate in specific amount capable of achieving the recited impurity limitation of not more than 18.5 ppm for smoking cessation, does not reasonably provide enablement commensurate in scope with the full breadth of the claimed invention without undue experimentation.
The claims are directed broadly to solid pharmaceutical compositions comprising:
i) varenicline, or a pharmaceutical acceptable salt,
ii) at least a scavenger agent of nitrite anion,
and iii) one or more pharmaceutically acceptable excipients or carriers,
wherein said composition has not more than 18.5 ppm of N-nitroso-varenicline impurity of the compound formula (II). with respect to varenicline.
The specification discloses only a limited number of working examples directed primarily to tablet formulations employing particular excipients such as microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Likewise, the examples utilize only limited scavenger systems, primarily ascorbic acid and ammonium chloride, under particular concentration ranges and testing conditions. However, the claims broadly encompass essentially any solid pharmaceutical composition containing any nitrite scavenger agent, and excipient systems capable of achieving the recited impurity limitation.
The determination of whether undue experimentation would have been required is guided by the factors set forth in in re Wands, 585 F.2d 731, 737 (Fed. Cir. 1998).
With respect to the breadth of the claims, the claims encompass a broad genus of solid pharmaceutical compositions without limitation to:
(i) a particular dosage form;
(ii) a particular scavenger agent;
(iii) a particular scavenger agent concentration;
(iv) a particular excipient system;
(v) a particular manufacturing process;
(vi) a particular storage conditions; and/or
(vii) particular packaging conditions.
Nevertheless, the specification only discloses a relatively small number of tablet embodiments utilizing specific excipient systems and limited scavenger agent.
With respect to the quantity of experimentation necessary, substantial experimentation would have been required to determine which combinations of scavenger agents, concentrations, excipient systems, packaging systems, and storage conditions would successfully achieve the claimed impurity limitation of not more than 18.5 ppm across the full scope of the claims.
With respect to the amount of direction or guidance presented, the specification provides limited guidance regrading:
(i) how to select suitable scavenger agents across the full claimed genus;
(ii) how to determine effective scavenger concentration;
(iii) hot differing excipient systems impact impurity levels; and
(v) how to reliably achieve the claimed impurity limitation across different solid pharmaceutical compositions.
Furthermore, the unpredictability of nitrite scavenger performance in pharmaceutical formulations is evidenced by Honsak et al. (Process 2022, 10, 2428, pages 1-18) expressly teaches that large differences in reactivity were observed between the different scavengers and further teaches that the nitrite scavenging activity does not directly translate into N-nitrosation inhibitor effectiveness. (See page 6, left column and page 1, Abstract.) Honsak additionally demonstrates that certain scavengers unexpectedly increase nitrosamine formation under some tablet conditions. For example, the references teaches that the other three evaluated scavengers (5, 7, and 16, respectively) increase the NMA amount and that sodium ascorbate (2) promoted N-nitrosation of PPxHcl to a significant degree during stress testing. (See page 9-10.)
The reference further demonstrates that nitrosamine formation and scavenger effectiveness are highly dependent upon formulation variables and testing conditions, including pH, humidity, temperature, excipient composition, storage conditions, and tablet environment.
Accordingly, the state of the prior art demonstrates that the behavior of nitrite scavengers in solid systems is unpredictable and highly formulation-dependent.
With respect to the present or absence of working examples, the specification contains only limited examples directed to specific tablet embodiments and does not provide representative examples commensurate with the full scope of the claimed genus of solid pharmaceutical compositions.
With respect to the nature of the invention and the state of the prior art, the art demonstrates substantial unpredictability regarding whether a given nitrite scavenger will successfully inhibit nitrosamine formation in a particular pharmaceutical composition and under particular storage conditions.
Therefore, one of ordinary skill in the art would have been required to engage in substantial experimentation to determine:
(i) which scavenger agents are suitable;
(ii) which scavenger concentration are effective;
(iii) which excipient systems are compatible;
(iv) which packaging systems are necessary; and
(v) which storage conditions permit achievement of the claimed impurity limitation across the full scope of the claims.
Such experimentation would have amounted to undue experimentation. Accordingly, the specification does not enable the full scope of the presently claimed invention.
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.
Claim(s) 1-8, 10-14, and 16-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (US2024/0374609A1) in view of Nanda et al. (Journal of Pharmaceutical Sciences 110 (08/14/2021) 3773−3775) and Combet et al. (Gut 2007;56:1678–1684).
Wei teaches a solid pharmaceutical composition comprising varenicline or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients/carriers for reducing nitrosamine impurity formation in varenicline pharmaceutical products. Wei expressly recognizes nitrosamine impurity as a problem associated with varenicline pharmaceutical compositions and teaches approaches to inhibiting nitrosamine formation. (See paragraphs [0001]-[0011].)
Wei teaches varenicline and pharmaceutically acceptable salts thereof including varenicline tartrate. (See paragraphs [0014]-[0015].) Wei further teaches solid pharmaceutical table formulations containing conventional pharmaceutical excipients, including microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium/crospovidone, colloidal silicon dioxide, and magnesium stearate. (See paragraph [0016] & Examples 1-4.) One of ordinary skill in the art would have understood Wei’s disclosure of colloidal silicon dioxide to encompass anhydrous colloidal silicon dioxide because pharmaceutical-grade colloidal silicon dioxide excipients including Aerosil® -type material, are conventionally utilized in anhydrous form in tablet formulation.
Wei additionally teaches incorporation of pharmaceutically acceptable acids for inhibiting nitrosamination reactions and expressly identifies suitable acids including tartaric acid, citric acid, malic acid, fumaric acid, and ascorbic acid (See paragraph [0064] & {0029].) Ascorbic acid encompasses the L-ascorbic acid the fact that ascorbic acid is a racemic mixture that include the L-isomer.
Wei Table 1 discloses a representative tablet formulation comprising:
Varenicline tartrate.
Microcrystalline cellulose,
Crospovidone,
Colloidal silicon dioxide,
Magnesium stearate, and
Tartaric acid.
Wei Table 1 specifically discloses approximately 3.42 mg tartaric acid in a tablet core weighing approximately 100 mg, corresponding to approximately 3.4 wt%. Wei further teaches the disclosed pharmaceutical compositions are useful for treating smoking cessation. (See paragraph [0045].) This value falls squarely within the claimed range of 0.5-20 wt%, 1-10 wt%, and 1.5-5 wt%>
Moreover, Wei expressly teaches the claimed impurity limitation. Specifically, Wei at paragraph [0039] discloses that the nitrosamine impurity in the pharmaceutical composition is not more than 7.5 ppm, including values of not more than 7.4 ppm, 7.3 ppm, 7.2 ppm, 7.1 ppm, 7.0 ppm, and lower values down to not more than 2.0 ppm. Because Wei’s disclosed impurity content of not more than 7.5 ppm is less than the presently claimed “not more than 18.5 ppm,” Wei teaches or renders obvious the claimed impurity limitation.
In conclusion, Wei teaches the following:
(i) a solid pharmaceutical composition;
(ii) varenicline or a pharmaceutically acceptable salt thereof, in this case, tartrate;
(iii) pharmaceutically acceptable excipients/carriers, in this case, microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium/crospovidone, colloidal silicon dioxide, and magnesium stearate;
(iv) acid additives for inhibiting the formation, in this case tartaric acid or ascorbic acid;
(v) tablet dosage forms; and
(vi) smoking cessation methods.
However, Wei does not expressly teach utilizing ascorbic acid as the nitrile scavenger agent in the exemplified tablet composition.
Nanda teaches that nitrile scavengers, including ascorbic acid (vitamin C), are useful for reducing nitrosamie formation in pharmaceutical compositions and solid dosage systems. Nanda further teaches ascorbic acid functions by reacting with nitrite species, thereby inhibiting nitrosamine reactions and reducing nitrosamine impurity formation. (See Abstract and pages 3373-3374.) Nanda additionally taches that nitrile scavengers may be incorporated into pharmaceutical dosage forms during manufacture and storage in order to suppress nitrosamine formation. (See Tables and page 3775.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute and/or select ascorbic acid from the finite list of pharmaceutically acceptable acids expressly disclosed by Wei for use in the solid varenicline tablet compositions of Wei because Wei already teaches:
(i) pharmaceutically acceptable acids useful for inhibiting nitrosamination;
(ii) expressly identifies ascorbic acid among the suitable acids species;
(iii) Nanda teaches ascorbic acid is a known nitrite scavenger useful for reducing nitrosamine formation in pharmaceutical systems; and
(iv) both references are directed to the same recognized problem of nitrosamine impurity formation in pharmaceutical products.
One of ordinary skill in the art would have been motivated to utilize ascorbic acid in the pharmaceutical compositions of Wei in order to reduce nitrosamine impurity formation, improve pharmaceutical stability, and satisfy recognized regulatory and safety concerns associated with nitrosamine impurities in pharmaceutical products.
Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success because Wei already teaches inhibition of nitrosamine formation using pharmaceutically acceptable acids, including ascorbic acid, while Nanda confirms the known nitrile scavenging properties of ascorbic acid in pharmaceutical systems.
To the extent additionally relied upon, Combet teaches that ascorbic acid reacts with nitrosating species and inhibits nitrosation reactions by reducing nitrosating intermediates (See pages 1628-1683), thereby decreasing nitrosamine formation. Accordingly, Combet further evidence that the introsation-inhibiting properties of ascorbic acid were well-known in the art.
Accordingly, the claimed invention as a whole would have been obvious to one of ordinary skill in the art at the time the invention was filed.
Conclusion
Claims 1-8, 10-14, and 16-18 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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