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 without traverse of Group I and species- arthritis, in the reply filed on 8/22/25 is acknowledged.
Claims 99-103 and 105-117 read on the elected species.
Upon further consideration, the requirement for election of species has been withdrawn and claims 99-117 have been considered for examiner.
Claim 118 has been withdrawn as being non-elected.
Claim Rejections - 35 USC § 112
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.
1. Claims 99-117 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated: “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Instant claimed method is directed to a method of treating or prophylactically treating a disease and/or alleviating the symptoms of a disease, comprising the step of orally administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a plurality of pellets, wherein each pellet has a smallest diameter ≤ 5 mm, and wherein each pellet comprises methotrexate or a pharmaceutically acceptable salt thereof. Thus, instant claimed method includes treating any disease or all the diseases with the composition comprising methotrexate pellets having a smallest diameter ≤ 5 mm. Instant claims not only recite treatment but also claim prophylactically treating a disease, which is a medical intervention or therapy designed to prevent a disease or condition from occurring. Thus, the term “prophylactic treatment” is construed to be “prevention”.
With respect to the description of the claimed invention in sufficient detail, it is noted that Applciants mention that the instant methotrexate composition is useful to treat arthritis, psoriasis, Crohn’s disease and/or a cancer selected among a breast cancer, a cancer vesicae urinariae, choriocarcinoma, a head and neck cancer, a lymphoma and a leukemia [0200-0203]. Applicants describes that 2.5 mg methotrexate tablet formulations are commonly known in the art, and that methotrexate is known for effectively treating inflammatory diseases such as arthritis, autoimmune diseases and cancer [0200-0203]. Applicants further describe the preparation of the claimed methotrexate pellets for providing at least 80% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 3 months or for 6 months. [0292] of the specification states that to achieve an IR formulation, mini tablets were coated with a HPMC film [0292 and Table 4]. Whereas Applicants describe the method of preparing instant methotrexate pellets and a method of achieving the claimed release rates, instant specification does not provide any correlation between the release rates achieved with methotrexate pellets having the smallest diameter of at least ≤ 5 mm and a method of treating, let alone prevent any diseases. While instant claims 101-104 recite specific diseases, Applicants have not provided any correlation for treating any type of cancer, given the breadth of the term “cancer” and instead merely states that the composition is useful for treating cancer. It is noted that Table 12 provides bioequivalence of SC injection and oral MTX at four different doses. Applicants have not provided any rationale to extrapolate the bioequivalence (Table 12) of methotrexate to an effective treatment of diseases i.e., any or all diseases. Applicants state that two or three release profiles can be selected to deliver the desired dose at intervals over the stomach and intestine i.e., releasing methotrexate between 15 minutes and 4 hours, obtained with mini tablets, without explaining how achieving the release rate would be effective in preventing any disease, including the claimed, that falls within the scope of instant method.
One skilled in the art would not be able to readily envisage that the methotrexate pellets having a smallest diameter of ≤ 5 mm, the dissolution rate of methotrexate and the bioequivalence studies described in the instant specification is effective in providing treatment of a huge genus encompassed by “a disease” or prevention of any disease because Applicants have not provided a nexus between the in vitro dissolution and in vivo efficacy of the composition. While the prior art recognizes that methotrexate is conventionally employed in treating arthritis, cancer, psoriasis or autoimmune disorders, one skilled in the art would not be able to readily determine that the claimed composition would indeed be effective in preventing any or all the diseases i.e., broad genus of diseases of instant claims, let alone treat the innumerable number of diseases that is within the scope of the diseases. The mere mention of the functional limitations i.e., the dissolution rates of methotrexate, does not satisfy the description requirement that applicants are in possession of the entire breadth of the invention because instant specification does not describe how to determine the parameters i.e., dose of methotrexate depending on the severity, age of the subject, duration of treatment., and the optimization of the said parameters to achieve the claimed dissolution rates (claims 111-114) and ensure an effective treatment or prevention of a huge genus of diseases. One of an ordinary skill in the art would not be able to predict the efficacy of the claimed composition, from the instant description, because the health conditions of a subject can vary widely based on risk factors such as genetic, environmental factors, lifestyle etc., and may include an individualized dose and/or duration of the treatment. In the absence of any guidance with respect to the treatment or prevention regimen, one skilled in the art would not be able to predict that a single composition is capable of preventing or provide treatment for an entire gamut of diseases. The level of skill and knowledge in the art is high.
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.
2. Claim 105 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.
Instant claim recites “twice within 8-12 hours once a week”, which is vague because it is unclear if applicants intend to claim administering twice within 8-12 hours and for one week or twice within 8-12 hours just for one day. For examination purpose, twice within 8-12 hours and for one week. Clarity and correction is requested.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
3. Claim(s) 99, 101-107, 109-110 and 115 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2006/0039985 to Bennett et al (Bennett).
Bennett teaches a powder containing methotrexate particles suitable for inhalation (abstract). [0003-0005] describes the use of methotrexate for inflammation, particularly antirheumatic, and cancer. Bennett describes that the methotrexate powder composition comprises particles effective to penetrate into the alveoli of the lungs, having a mass median diameter is less than about 10 micron, 1.0 to 5 micron, and preferably less than 5 micron diameter [0019 and 0085-0086].
Instant claims recite that the pellet has a smallest diameter ≤ 5 mm, which includes the micron sizes of particles. Further, instant specification defines a “pellet” as a rounded, spherical or cylindrical body or medicine. Applicants describe a pellet to comprise a small ball or tube-shaped piece of any substance, may also refer to a small tablet, i.e. a minitablet, granulate, or multiparticulates. Further, it is described that a pellet of the present invention is preferably spheronized or spherical but may in principle have another suitable shape. Instant specification (p 5, l 20-23) defines the term “smallest diameter” means that the pellet is able to pass through a circular aperture with this diameter, e.g. in the case of a cylindrical body it may be the diameter of the body, and the term diameter does not necessarily imply that the pellet is spherical. The above definition does not exclude a particle .
Thus, the particles of Bennett, having a particle size of less than 10 micron, read on the instant pellet having a smallest diameter of less than ≤ 5 mm of claims 99 and 110. Bennett teaches administering the composition comprising methotrexate particles to a patient [0013] in a therapeutic effective amount [0037], for treating individuals suffering from rheumatoid arthritis, psoriasis, cancer etc [0098].
For claims 105-107, Bennett teaches the composition contained within a hard capsule [0094] and administered on different dosing schedules including once a week [0062]. Further, Bennett teaches packaging the microparticle powder in a capsule and therefore meets as few as 11 particles of claim 115 (Pellets interpreted as particle, see above). For claim 115, Bennett teaches that the composition further comprises an excipient [0025], such as sugars, amino acid, etc [0036, 0068-0069 and 0074].
Thus, Bennett anticipates instant claims.
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.
4. Claim(s) 99-107 and 109-117 are rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0039985 to Bennett et al (Bennett).
Bennett has been discussed above for claims 99, 101-107, 109-110 and 115. Bennett fails to explicitly teach the instant claims 111-114 and 116-117.
However, Bennet suggests that the methotrexate compositions include polymeric excipients such as polymeric excipients/additives such as polyvinylpyrrolidones, hydroxypropyl methylcellulose etc [0075]. Bennett teaches preparing the composition wherein methotrexate is encapsulated, and further the composition is prepared for immediate release [0075]. Further, Bennett teaches a range of therapeutically effective dose of 0.001 mg/kg/dose to 100 g/mg/dose and suggests optimizing the dose based on several factors such as the nature and severity of the indication being treated, the desired response, the patient population, condition of the patient etc [0060-0061]. Therefore, it would have been obvious before the effective filing date of the instant invention to prepare the methotrexate composition of Bennett as an encapsulated, immediate release preparation by choosing the suitable excipients/additives and further optimize the amount of methotrexate, to treat patient of any age, including children and younger adults. One of an ordinary skill in the art would have been motivated to do so because Bennett prefers an immediate release composition of methotrexate as opposed to a sustained release composition and accordingly, choosing the amount of active and the suitable excipients with an expectation to provide the desired release would have been within the scope of one of an ordinary skill in the art. Further, one of an ordinary skill in the art would be motivated to administer the composition to any age subject because Bennett does not restrict administering to any group of subjects. Thus, one skilled in the art would have expected that the composition would be effective any age of the subjects.
5. Claim(s) 99-110 and 115-117 are rejected under 35 U.S.C. 103 as being unpatentable over WO 98/22095 to Kelm et al., in view of US 2006/0039985 to Bennett et al (Bennett) and Hypromellose (Ataman Chemicals, 2015- 8 pages).
Kelm teaches a pharmaceutical composition comprising an effective amount of an active agent and in the form of a tablet or a capsule, with a maximum diameter of 3 mm to about 10 mm, and an enteric polymer coating (abstract, Page 5- summary of the invention). Kelm teaches several active agents including the claimed methotrexate (page 8, 2nd full para). Page 9 describes inclusion of excipients in the composition (last para). For the instant coating, Kelm teaches hydroxypropyl methylcellulose (p 11, 1st full paragraph). Examples 1-3 teach preparation of a coated dosage form. The diameter taught by Kelm overlaps the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, one of an ordinary skill in the art would have been able to optimize the size of 3-5 mm and still achieve an effective pharmaceutical composition for drug delivery.
Kelm suggests methotrexate for inflammation but does not explicitly teach the claimed method.
Bennett teaches a powder containing methotrexate particles suitable for inhalation (abstract). [0003-0005] describes the use of methotrexate for inflammation, particularly antirheumatic, and cancer. Bennett describes that the methotrexate powder composition comprises particles effective to penetrate into the alveoli of the lungs, having a mass median diameter is less than about 10 micron, 1.0 to 5 micron, and preferably less than 5 micron diameter [0019 and 0085-0086]. For claims 105-107, Bennett teaches the composition contained within a hard capsule [0094] and administered on different dosing schedules including once a week [0062]. Further, Bennett teaches packaging the microparticle powder in a capsule and therefore meets as few as 11 particles of claim 115 (Pellets interpreted as particle, see above).
Bennett teaches a range of therapeutically effective dose of 0.001 mg/kg/dose to 100 g/mg/dose and suggests optimizing the dose based on several factors such as the nature and severity of the indication being treated, the desired response, the patient population, condition of the patient etc [0060-0061]. Therefore, it would have been obvious before the effective filing date of the instant invention to prepare the composition of Kelm, by including methotrexate as the active agent, and employ for treating arthritis, psoriasis etc., because Kelm suggests methotrexate as a suitable active agent and further Bennett teaches that methotrexate is effective for treating arthritis, cancer and psoriasis. Further, one of an ordinary skill in the art would have been motivated to employ methotrexate, in optimum to treat arthritis, psoriasis and cancer, and further suitable excipients with an expectation to provide the desired release. Further, one of an ordinary skill in the art would be motivated to administer the composition to any age subject because Bennett does not restrict administering to any group of subjects.
Kelm does not teach white pills of claim 108. However, Kelm teaches hydroxypropyl methylcellulose for coating of the methotrexate composition.
In this regard, Hypromellose document describes that HPMC used for water-soluble film used for coating (film) is in the form of white powder or granules (page 1 – 7th para). Hence, it would have been obvious for one of an ordinary skill in the art before the effective filing date of the instant invention that the coating with HPMC taught by Kelm would result in a white methotrexate composition.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKSHMI SARADA CHANNAVAJJALA whose telephone number is (571)272-0591. The examiner can normally be reached Generally M- F 9 AM to 6 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LAKSHMI S CHANNAVAJJALA/ Primary Examiner, Art Unit 1611