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 .
Response to Amendments
Applicant’s amendments to the claims of March 16, 2026, in response to the Office Action of September 16, 2026, are acknowledged.
Response to Arguments
Applicant’s arguments and allegations have been thoroughly considered by the examiner. New claims are amended to require mannitol as bulking agent in a liquid formulation. A response is set forth below and a suggestion for allowance is set forth at the end of the Examiner’s response to Applicant’s arguments.
Applicant argues that the claimed concentration of citrate buffer and pH is not obvious and is critical. Applicant argues that Husfeld does not teach a concentration of buffer and Usach teaches common formulations to be in the range of 5-15 nM. Applicant acknowledges that the prior art states that using a citrate buffer concentration below 7.3 mM is advantageous and so it means that a concentration of 5 mM to 7.3 mM would be used by a POSA.
The examiner notes that unexpected results in the form of a criticality of an associated range has not been made of record. To show a criticality, Applicant To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
The examiner does not see data or a showing as compared to the closest prior art that is commensurate in scope with the breadth of the claims. As such, he is determining if a prima facie showing is established for the record.
With respect to Applicant’s allegations that the prior art teaches 7.3 nM or less citric acid, which means 5 mM to 7.3 mM because the context of Usach is that citric acid is commonly used in a range of 5 to 15 mM, the examiner responds.
The examiner notes that the context of this statement supports the use of the claimed range of 0.2 to 2 mM citrate buffer and a range below 7.3, including below 5-15 nM for the following reasons. The number 7.3 nM comes from page 2993, 1st full par., wherein citrate buffer was used with an API. The context is that injection related pain was noted at a concentration of 7.3 to 10 mM and so using less than this to avoid pain sensitization is taught. See p2993, 4th full par. Not only is there no lower bound as intimated by Applicant, but the best example of limited or no injection site pain was shown at the claimed range and well below 5nM. In particular, Usach also teaches when a lower amount of citrate buffer is used, pain can be prevented or minimized. A formulation with 1.2 mM citrate buffer alleviated pain from injection in all but a low percentage of subjects. See p2993, 1st full par. In context, using the least amount of citrate buffer possible is advantageous and amounts as low as 1.2 mM are most effective to avoid injection pain associated therewith. Not only is the only example provided in which less than 5 mM was used and the amount falls within the claimed range, but in context of Usach, a POSA would understand that 5 mM is not a minimum requirement and less than 7.3 mM does include the lowest dose necessary. A POSA would consider using 1.2 mM and as the lowest amount possible as taught. Usach notes that injection osmolality should remain below 600 mOs/kg.
With respect to the new limitation of mannitol in a liquid formulation, the examiner applies Mehmood et al., below. Husfeld does teach lyophilized formulations as well as their reconstitution into sterile injectable solutions or dispersions. See par.’s 308 360. Husfeld does not teach a liquid form with mannitol nor selecting mannitol.
The examiner applies Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015. Mehmood teaches excipients that are advantageous for lyophilized and parenteral formulations. Mannitol is the most commonly and widely used excipient in lyophilized products. It has a very high eutectic melting temperature after crystallization and an amorphous bulking agent is preferred. Further, crystallization of buffer components can lead to degradation of API. Citrate buffer was found to be the most preferred as it remained amorphous during lyophilization. See p21, 2nd full par. Thus, a POSA would use mannitol and citrate buffer in a liquid preparation of lyophilized drug for reconstitution.
Jacobson, (US2010/0273886) teaches lyophilized produces in liquid solutions. See Abstract. Further, improved methods for lyophilizing a wider range of materials and using particularly desired types of materials in lyophilization. See par. 16. In Example 1, mannitol is used as a bulking agent at a concentration of 0.4 mg/ml mannitol. See Example 1. In an exemplary formulation, mannitol is the bulking agent. See Table 7. Jacobson teaches using mannitol and the pH may be lowered with an acid after the API is dissolved. See par. 26. Mannitol is a preferred bulking agent as it is used in most examples and described throughout Jacobson. See par.’s 30, 31, 36, 37, 39, and others.
The prior art above teaches composition comprising the claimed components. The osmolality is well-known for injectable composition and mannitol and citrate buffer appear to be the most commonly used and beneficial excipients in lyophilized and reconstituted formulations. Further, the amount of citrate buffer is provided at a claimed dosage in an example provided as the most beneficial to avoid an adverse event of injection. The lowest amount possible is optimizable. Further, an example provided by Jacobson uses 0.4 mg/ml mannitol. Thus, without a showing of unexpected results, it is prima facie obvious to a POSA to arrive at the claimed liquid formulation through reconstitution of a lyophilized product, e.g., and to include citric acid and mannitol and to start dose titration and optimization based on the teachings of the cited prior art.
Consistent with the response set forth above and no new arguments traversing the DP rejections, the DP rejections are maintained at this time.
Suggestions for Allowance:
The examiner suggests Applicant reach out to the examiner as potentially narrowing the claimed to include a close-ended transitional phrase and requiring ratios and percentages of claimed components consistent with the examples provided in the instant Specification can put the instant application in condition for allowance. Double Patenting rejections must be reconsidered in light of any amendments to the claims.
Status of the Claims
Claims 30, 33, 57, 58, and 88-97 are pending and examined.
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.
Claims 30, 33, 57, 58, and 88-97 are rejected under 35 U.S.C. 103 as being unpatentable over Husfeld et al., (US2017/0260131), in view of Usach et al., “Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site,” Adv Ther (2019), and in view of Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015, and in view of Jacobson, (US2010/0273886)
Husfeld teaches compounds that modulate TRPV1 activity and this includes Example 7, (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-((methylamino)methyl)piperidine-1-carboxylate. See par. 411. Prodrugs are designed to improve solubility, pungency, rapid or delayed delivery. See par. 28. The capsaicin has a release rate controlled through pH because pH controls the intramolecular cyclization-release reactions. See par. 30.
In some embodiments, the buffer provides a time window where turnover to parent drug is significantly delayed until the return of physiological conditions. In some embodiments, the release of parent drug is tuned to provide for rapid release based on the rate of the intramolecular cyclization release. In some embodiments, the release of parent drug is tuned to provide for delayed release based on the rate of the intramolecular cyclization release.
Dosage forms can be solid and can include fillers such as lactose and mannitol. See par. 320. Liquid formulations are also contemplated. See par. 349. Pain to be treated includes pain from surgery, nerve injury, cancer, trauma, and many others. See par. 24. Daily dosages include an amount of 0.01 mg/kg to 30 mg/kg. See par. 378. Buffers that were used to test the effects of cyclization release including salts of tartrate, glycine, citrate, and others. See par. 425. Routes of administration can be oral, parenteral, and others. See par. 23. Subcutaneous route of administration is also taught. See par.’s 23, 308, 309, and 360. The recited non-salt form is the free base. Salt forms are also contemplated.
Usach teaches, “Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300 mOsm/kg) and no more than 600 mOs/kg have been used in order to prevent pain.” Common buffers that are added to parenteral formulations to adjust pH includes citrate, phosphate, and acetate. See p2992-2993, bridging par. Citrate buffer is commonly used in parenteral formulations at a concentration of 5-15 mM. See p2992. Table 2 provides for buffers that can be used in parenteral preparations and their approximate buffering ranges. The ranges for citrate include 2.1-6.2. A pH close the physiologic one is recommended to minimize pain, irritation, and tissue damage. Further, the concentration of citrate buffer should kept as low as possible and below 7.3 mM to avoid increased pain. See Abstract.
Mehmood teaches excipients that are advantageous for lyophilized and parenteral formulations. Mannitol is the most commonly and widely used excipient in lyophilized products. It has a very high eutectic melting temperature after crystallization and an amorphous bulking agent is preferred. Further, crystallization of buffer components can lead to degradation of API. Citrate buffer was found to be the most preferred as it remained amorphous during lyophilization. See p21, 2nd full par. Thus, a POSA would use mannitol and citrate buffer in a liquid preparation of lyophilized drug for reconstitution.
Jacobson teaches lyophilized produces in liquid solutions. See Abstract. Further, improved methods for lyophilizing a wider range of materials and using particularly desired types of materials in lyophilization. See par. 16. In Example 1, mannitol is used as a bulking agent at a concentration of 0.4 mg/ml mannitol. See Example 1. In an exemplary formulation, mannitol is the bulking agent. See Table 7. Jacobson teaches using mannitol and the pH may be lowered with an acid after the API is dissolved. See par. 26. Mannitol is a preferred bulking agent as it is used in most examples and described throughout Jacobson. See par.’s 30, 31, 36, 37, 39, and others.
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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Husfeld and Usach. One would be motivated to do so because Husfeld teaches the claimed API with a buffer for a common use and teaches the buffer can be used to adjust the release rate of the API because it tunes the rate of intramolecular cyclization release, which is pH-dependent. In view of the known result-effective nature of a buffer in a composition comprising the claimed API, it would be highly optimizable through nothing more than routine experimentation. Further, Usach teaches the claims osmolarity to be ideal to prevent pain and the typical buffers used include those claimed and using citrate, e.g., with a pH close the physiologic one is recommended to minimize pain, irritation, and tissue damage. Lower amounts of buffer are also motivated. As such, there was a reasonable and predictable expectation of success in arriving at the claimed methods and products in view of the teachings of Husfeld and Usach. There is no reason that specific forms of post-surgical pain would be excluded from treatment in view of the teachings to treat many forms of post-surgical pain.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 10-12, 16, 30, 33, 57, 58, 70-73, and 87 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,821,105, in view of Husfeld et al., (US2017/0260131), in view of Usach et al., “Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site,” Adv Ther (2019), and in view of Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015, and in view of Jacobson, (US2010/0273886). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘105 patent are directed to a method of using the same API to treat pain that is secondary to different claimed surgical procedures. Those claims do not include a buffer and are broader than the instant claims. However, the use of a buffer is also contemplated in the Specification and open-ended claim language of the ‘105 patent. Moreover, in view of Husfeld and Usach and for the reasons set forth above, a buffer can be used to tune the release rate of the claimed active.
Claims 1-8, 10-12, 16, 30, 33, 57, 58, 70-73, and 87 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,464,767, in view of Husfeld et al., (US2017/0260131), in view of Usach et al., “Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site,” Adv Ther (2019), and in view of Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015, and in view of Jacobson, (US2010/0273886). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘767 patent are directed to a method of using the same API to treat pain that is secondary to different claimed surgical procedures. Those claims do not include a buffer and are broader than the instant claims. However, the use of a buffer is also contemplated in the Specification and open-ended claim language of the ‘767 patent. Moreover, in view of Husfeld and Usach and for the reasons set forth above, a buffer can be used to tune the release rate of the claimed active.
Claims 1-8, 10-12, 16, 30, 33, 57, 58, 70-73, and 87 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,634,384, in view of Husfeld et al., (US2017/0260131), in view of Usach et al., “Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site,” Adv Ther (2019), and in view of Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015, and in view of Jacobson, (US2010/0273886). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the 384 patent are directed to treating pain with the claimed agent. The claims agent is within a genus of formula, but is taught as compound 7 as a preferred embodiment of the structure of claim 1. The utility is generically claimed to treat pain in claim 6. The claims of the ‘384 patent do not include a buffer and are broader than the instant claims. However, the use of a buffer is also contemplated in the Specification and open-ended claim language of the ‘384 patent. Moreover, in view of Husfeld and Usach and for the reasons set forth above, a buffer can be used to tune the release rate of the claimed active.
Claims 1-8, 10-12, 16, 30, 33, 57, 58, 70-73, and 87 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,359,316, in view of Husfeld et al., (US2017/0260131), in view of Usach et al., “Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site,” Adv Ther (2019), and in view of Mehmood et al., “Excipients Use in Parenteral and Lyophilized Formulation Development,” Open Science Journal of Pharmacy and Pharmacology July 20, 2015, and in view of Jacobson, (US2010/0273886). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘316 patent are directed to the claimed agent. The use and utility is to treat pain is set forth throughout the Specification. The claims of the ‘316 patent do not include a buffer and are broader than the instant claims. However, the use of a buffer is also contemplated in the Specification and open-ended claim language of the ‘316 patent. Moreover, in view of Husfeld and Usach and for the reasons set forth above, a buffer can be used to tune the release rate of the claimed active.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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