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 .
Claim Objections
Claims 1 and 9 are objected to because of the following informalities:
Claims 1 and 9 recite the abbreviation “NLT” without indicating what the abbreviation means. The Examiner suggests amending the claims to recite the full term (i.e., no less than) with the abbreviation in parentheses in the first instance that such appears in the claims.
Claims 1 and 9 also recite “80%Q”. The Examiner suggests deleting the Q or indicating what the Q stands for.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-10 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is unclear. Claim 1 recites: “…stable during accelerated stability”. It is not clear what is meant by “accelerated stability”. Does “accelerated stability” mean that the conditions in the stability analysis are extreme (e.g., high heat, high humidity)? If such is the case, the experimental conditions need to be clarified. The terms “stable” and “accelerated stability” in claim 1 are relative terms which render the claim indefinite. The terms “stable” and “accelerated stability” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 2 recites the limitation "the anti-caking and suspending agent". There is insufficient antecedent basis for this limitation in the claim. Claim 2 depends from claim 1, which recites “at least one anti-caking and suspending agent” which encompasses multiple anti-caking and suspending agent, (emphasis added). Thus, it is unclear whether just one, more than one, or all of the anti-caking and suspending agents are being referenced and must be silicified microcrystalline cellulose. Amending claim 2 to recite “wherein the at least one anti-caking and suspending agent is…”, would overcome this rejection.
Claim 3 recites the limitation "the viscosity building agent". There is insufficient antecedent basis for this limitation in the claim. Claim 3 depends from claim 1, which recites “at least one viscosity building agent”, which encompasses multiple viscosity building agents. Thus, it is unclear whether just one, more than one, or all of the viscosity building agents are must be carboxymethylcellulose or its salts. Amending claim 3 to recite “wherein the at least one viscosity building agent is…”, would overcome this rejection.
Claim 10 is unclear. Claim 10 recites “is stable at normal and accelerated stability storage conditions”. Similar to the above rejection, it is not clear what is meant by “accelerated stability storage conditions”. Based on this phrase, one of ordinary skill in the art does not know which storage conditions were “accelerated” and to what extent. The experimental conditions need to be clarified. The terms “stable”, “normal” and “accelerated stability storage conditions” in claim 10 are relative terms which render the claim indefinite. These terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 2-10 depend from claim 1, and have thus been included in the rejection.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 recites a broader pH range (“between 5 and 6.5”) than the pH range recited in independent claim 1 (“between 5.5 and 6.5”). Claim 8 is dependent on claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Sudhakar et al. (US 2020/0383911; published: 12/10/20), in view of Margolin (US 6,956,044; published: 10/18/05) and Mandadapu et al. (EP 3494965; published: 6/12/19).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Sudhakar et al. is directed to topiramate oral liquid suspension and use thereof (Title).
With regards to instant claims 1-6, Sudhakar et al. teach an oral liquid suspension comprising: topiramate (D90 ≤ 200 microns, D50 ≤ 100 microns and D10 ≤ 30 microns), water, glycerin, propylene glycol, polyethylene glycol, methylparaben, sodium benzoate (i.e., the preservative), sorbitol (i.e., the solvent), saccharin (i.e., the sweetener), sucralose, xanthan gum, carboxymethyl cellulose (i.e., the at least one viscosity-building agent), sodium phosphate and PROSOLV® SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide; the at least one anti-caking and suspending agent) (See entire reference; e.g., claims 1 and 3-4).
With regards to instant claims 1 and 7, Sudhakar et al. teach that in specific embodiments, the oral suspension includes the flavoring agent cherry flavor, natural and artificial ([0163]).
With regards to instant claim 1, Sudhakar et al. teach that the oral liquid suspension exhibits redispersibility; such that upon turning over 3 times, the oral liquid suspension exhibits at least 80%, 85%, 90% or 95% redispersibility ([0216-0220]).
With regards to instant claims 1 and 9, Sudhakar et al. teach that the oral liquid suspension exhibits in-vitro dissolution rate more than 85% or 88% of drug release within 30 minutes, when said composition is placed in a dissolution vessel filled with 900 mL of 0.1N HCl, pH 1.2 maintained at 37+/- 0.5 °C and stirred at a paddle speed of 50 rpm using a USP Type II (paddle) apparatus ([0221-0222]).
With regards to instant claims 1 and 10, Sudhakar et al. teach that the oral liquid suspension is relatively stable ([0011]). More specifically, Sudhakar et al. teach that the suspending agent contributes to the stability; less than about 0.1 wt% of the active agent is decomposed over the period of time of manufacturing, shipping, and storage of the oral liquid suspension (e.g., up to 6-9 months) under ambient conditions ([0028]). Such reads on the limitations of instant claims 1 and 10, especially in view of the indefiniteness (see 112b rejection); with lack of clarity, one of ordinary skill in the art would understand that the stability test was conducted under room temperature conditions and any amount of stability could read on the unclear value of stability.
Ascertainment of the Difference Between the Scope of the Prior Art and Claims
(MPEP §2141.012)
Sudhakar et al. do not teach the claimed viscosity range of 75-200 cP, as required by instant claim 1. However, Sudhakar et al. teach the term “viscosity-increasing agent” refers to a substance added to products, such as oral liquid suspensions, to increase the viscosity and is used in order to impart an appropriate viscosity to the oral liquid suspension ([0025]).
Sudhakar et al. do not teach the claimed pH range of 5.5-6.5 or 5-6.5, as required by instant claims 1 and 8. However, Sudhakar et al. teach that achieving a suitable stability of the suspended active ingredient is achieved in part by modifying the pH of the composition ([0011]).
Sudhakar et al. do not teach wherein the oral liquid suspension contains pirfenidone in about 5-10 wt%, as required by instant claim 1. However, such deficiency is cured by Margolin.
Margolin is directed to composition and methods for treatment of epilepsy, just like Sudhakar et al. (Title). Margolin teaches that pirfenidone possesses remarkable anti-convulsant properties in widely accepted experimental models of epileptic seizures (col. 4, lines 18-21).
Sudhakar et al. and Margolin do not teach wherein the pirfenidone in the oral liquid suspension has a particle size distribution of D10 < 30 microns, D50 < 100 microns and D90 < 300 microns, as required by instant claim 1. However, such deficiency is cured by Mandadapu et al.
Mandadapu et al. is directed to an improved process for the preparation of pirfenidone (Title). Mandadapu et al. teach that the particle size distribution (PSD) of the drug substance may have significant effects on final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.) ([0007]). Mandadapu et al. teach a reduction of particle size process using a colloid mill, wherein the resulting pirfenidone has a particle size distribution of D10 less than 50 µm, preferably less 20 µm; D50 less than 100 µm, preferably 50 µm; D90 less than 200 µm, preferably 100 µm ([0057] and Example 1). Mandadapu et al. teach a pharmaceutical composition comprising pirfenidone prepared by such abovementioned process and at least one pharmaceutically acceptable excipient and such composition may be administered to a mammalian patient in any dosage form (e.g., liquid) ([0075]).
Sudhakar et al., Margolin and Mandadapu et al. do not specifically teach the wt% of pirfenidone (e.g., about 5 to about 10 wt%), as required by instant claim 1.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
The oral liquid suspension pH, wt% of pirfenidone and viscosity is clearly a result effective 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 and would reasonably expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pH, amount of active agent pirfenidone and viscosity in order to best achieve the desired results as such would provide advantageous liquid suspension thickness for oral administration, biological effect and suitable stability. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). The Examiner considers it prima facie obvious to optimize the amounts of any biologically active agent (e.g., pirfenidone) to achieve their known biological effect, absent unexpectedly superior properties of the claimed invention. In the instant case, Sudhakar et al. teach the term “viscosity-increasing agent” refers to a substance added to products, such as oral liquid suspensions, to increase the viscosity and is used in order to impart an appropriate viscosity to the oral liquid suspension ([0025]). Sudhakar et al. teach that achieving a suitable stability of the suspended active ingredient is achieved in part by modifying the pH of the composition ([0011]). In the instant case, one of ordinary skill in the art would have recognized that the viscosity and pH of the abovementioned oral liquid suspension would impact the oral administration and stability and therefore be an optimizable variable.
Based on the teachings and Sudhakar et al. and Margolin, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine two compositions, each of which is taught by the prior art to be useful for the same purpose (topiramate + pirfenidone for the purpose of providing anti-convulsant actions in an oral liquid suspension), in order to form a third composition to be used for the very same purpose (See MPEP 2144.06-I). Alternatively, based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (topiramate with pirfenidone for the purpose of providing anti-convulsant actions in an oral liquid suspension) (See MPEP 2144.06-II).
Margolin et al. and Mandadapu et al. are both directed to pirfenidone used in pharmaceutical compositions. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the composition taught by Sudhakar et al. and Margolin by incorporating the particles of pirfenidone with the same claimed particle size distribution as taught by Mandadapu et al. ([0075]) to achieve the predictable result of obtaining a composition suitable for being administered to humans and provide an anti-convulsant effect. One of ordinary skill in the art would have been motivated to do so because Mandadapu et al. teach that it is advantageous for final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.) ([0007]). Furthermore, the particle size distributions of both drug substance and excipients can affect drug product manufacturability (e.g., flowability, blend uniformity, compactibility, etc.), which, ultimately, can impact safety, efficacy, and quality of the drug product ([0007]).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the invention was effectively filed, as evidenced by the references, especially in the absence of evidence to the contrary.
Thus, the claimed invention was prima facie obvious before the effective filing date of the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GENEVIEVE S ALLEY whose telephone number is (571)270-1111. The examiner can normally be reached Monday-Friday 8:00-5:00.
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, David Blanchard can be reached at 571-272-0827. 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.
/GENEVIEVE S ALLEY/ Primary Examiner, Art Unit 1617