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 .
Amended claims 1-4, 6-7, 9-11, 14, 17, 20 and 23-29 and new claim 44 are pending. Claim 34 remain withdrawn.
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.
Claim(s) 1-4, 6-7, 9-11, 14, 17, 20 and 23-29 and claim 44 are rejected under 35 U.S.C. 103 as being unpatentable over Schwebel WO2017067980 (hereinafter Document D1 or D1); Haldar US2020179313 (hereinafter Document D2 or D2); Tong US 20200268705 (hereinafter Document D3 or D3); Dhawan, Pharmaceutical Technology MAY 2005 Vol: 29 Issue: 5, 72-80. Brewster, Pharmazie. 2002 Feb;57(2):94-101; Brady, Chapter 7 Developing Solid Oral Dosage Forms, Polymer Properties and Characterization, 2017 and Parveen, European Journal of Pharmacology 670 (2011) 372–383.
Document D1 discloses (page 1, paragraph 1; page 3, paragraph 5-6; page 6,
paragraph 6 - page 9, paragraph 6; page 10, paragraph 5; page 11, paragraph
3- page 12, paragraph 4; page 15, paragraph 5 - page 16, paragraph 5; examples: (aqueous or dried) composition comprising dantrolene (salt) and cyclodextrin (preferably a 13-cyclodextrin, having a molar substitution of 0.05 to 10), wherein the pH of the composition is greater than 7, wherein the molar ratio of dantrolene to cyclodextrin is 1:2 to 1:30. The aqueous composition comprises an aqueous diluent e.g. water, C1-6 alcohols, polyethylene glycol. The composition can be formulated in a kit, is suitable for injection, and for use in treating malignant hyperthermia.
D1 is silent on the molecular weight of polyethylene glycol (however, see point 5.2) and the use of polyethylene glycol in reducing foaming in a formulation.
As such the difference is that in D1 does not teach that the polyethylene glycol is as specified to have an average molecular weight in the range 1500 to 6000, whereas D1 is silent on this.
Document D2 discloses (page 1, paragraph 0009-0024; page 3, paragraph 0056 - page 4, paragraph 0062; page 4, paragraph 0069-0070; page 4, paragraph 0074 - page 5, paragraph 0082; page 10, paragraph 0149) pharmaceutical compositions comprising a hydrophobic drug, cyclodextrin, and polyethylene glycol and/or propylene glycol. In the examples, 2-hydroxypropyl-13-cyclodextrin (HPBCD) was used to enhance the solubility and bioavailability of hydrophobic compound, e.g. vorinostat. PEG was used to facilitate release of the drug from HPBCD and improve bioavailability.
D2 does not disclose dantrolene.
Likewise, Document D3 discloses (page 2, paragraph 001-0013; page 2, paragraph 0020 - page 3, paragraph 0024; examples: injectable composition of the hydrophobic drug cabazitaxel. The composition comprises cabazitaxel, cyclodextrin (e.g. sulfobutyl ether-!3-cyclodextrin), solubiliser polyethylene glycol (PEG) and polyvinylketone (PVP). These components were found to significantly improve the property of the cabazitaxel preparation and can effectively increase the solubility and stability (in terms of precipitation) of cabazitaxel. D3 does not disclose dantrolene.
Taken together, the critical issue here is the molecular weight of base claim. Also see section under 112-2 for the range. The effect of this difference as alleged to the reduction of foaming. The application shows that the use of PEG to prepare a formulation in more foam formation than preparing the formulation without PEG (see Table 4, Formulation 1). PEGs are widely applied in pharmaceutical formulations for many reasons, also in compositions comprising hydrophobic actives and cyclodextrin. For example, D2 discloses that PEG was used to facilitate release of the drug from HPBCD and improve bioavailability. D3 describes the use of PEG to effectively increase the solubility and stability (in terms of precipitation) of a formulation comprising hydrophobic active and cyclodextrin. The occurrence of foaming is not reported. Being aware of the versatility of PEG in such formulations, the skilled person would therefore regard it as a normal option to use PEG for stabilizing formulations, among which prevention of precipitation, degradation and foam formation, in order to solve the problem posed.
Dependent claims:
claims 3, 6, 7, 9, 10 and new claim 44 drawn to choice of different (modified/substituted) cyclodextrins; claim 11 drawn to amount of cyclodextrins;
claim 14 drawn to choice of different PEG
claim 17 amount of P{EG
claim 27 amount of (ratios) of drug to cyclodextrins to PEG
claim 23 dry; Claim 25 lyophilized; Claim 26 pH
These limitations (see Dhawan, Parveen, Brewster and Brady below for more) and claims which dependent on these, are within the repertoire of one of skill in the art for routine optimization as noted in the above citations in generic terms (see highlights above). All these relate to selective combination of known elements used/applied in pharmaceutical art. It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known in the art for their beneficial properties. Again, the invention is a selective combination of the inventions by the prior arts done in a manner obvious to one of ordinary skill in the art. Patent for the combination of known elements wherein their functions remain the same withdraws “what is already known into field of its monopoly and diminishes resources available to skilled men”. Sakraida v. Ag Pro, Inc.189 USPQ 449, 425 US 273, (1976). It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The 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).
Brewster is invoked here for the use of chemically modified cyclodextrins in the development of formulations for chemical delivery systems. According to Brewster (see conclusion), chemically modified CDs offer unparalleled versatility, allowing the design of molecular systems tailored for solubilization, delivery, sensing, or separation, far beyond the capabilities of natural CDs alone.
See section under Natural vs. Chemically Modified Cyclodextrins (CDs): While native CDs have desirable inclusion properties, their use is constrained by several limitations, including low solubility (notably for β-CD), non-specificity in binding, and variable safety profiles at higher doses. Chemically modified CDs (CM-CDs) have been developed to overcome these limitations by introducing functional groups that alter their physicochemical and pharmacokinetic properties.
Hydroxypropyl-β-cyclodextrin (HP-β-CD) is one of the most important derivatives, prepared by reacting β-CD with propylene oxide. The hydroxypropyl groups increase aqueous solubility to over 50 g/100 mL and reduce crystallinity, enabling better complexation and easier formulation in aqueous systems. HP-β-CD is approved for parenteral, oral, and ocular use, with applications in solubilizing poorly soluble drugs such as dexamethasone and itraconazole.
Methylated-β-CD (M-β-CD) features methylation at the hydroxyl positions. Depending on the degree of substitution, methylation improves solubility and inclusion efficiency. However, complete methylation can lead to cytotoxicity and membrane lysis, especially in parenteral applications. Randomly methylated CDs (RM-β-CD) are used primarily in analytical chemistry, especially in chiral separation techniques such as capillary electrophoresis.
Sulfobutyl ether-β-CD (SBE-β-CD) introduces negatively charged sulfonate groups, significantly enhancing solubility and adding electrostatic interaction capabilities. SBE-β-CD has high biocompatibility and is used in several FDA-approved injectable products, such as voriconazole. The anionic nature of SBE-β-CD also improves complexation with cationic drugs.
Other functionalized CDs include carboxymethyl-, acetyl-, amino-, and polymer-bound derivatives, each with specific benefits (Figure 7). Importantly, each modified CD must be rigorously evaluated for toxicity, metabolism, and excretion pathways. Regulatory acceptance varies by country and application route, and safety profiles are contingent on substitution patterns, degrees of substitution, and residual reagents from synthesis.
Dhawan, Brady and Parveen are invoked here for the choice of PEGs. Dhawan titled ‘High Molecular Weight Poly(ethylene oxide)-Based Drug Delivery Systems’ teaches that Various grades of high molecular weight PEO are available that can be selected depending upon the nature of active pharmaceutical agent and delivery system required (see column B, page 79. Brady teaches the selection and characterization of polymeric materials as pharmaceutical excipients. It explores key polymer properties—including molecular weight, glass transition temperatures, and mechanical strength—crucial for controlled release, bioavailability enhancement, and structural formulation. PEGs such as CARBOWAX™ SENTRY™ Polyethylene Glycol 3350 are commercially available that fall under the scope of the range of base claim 1. These solid water-soluble polymer with excellent solvency for substances that do not readily dissolve in water and help to increase viscosity of a solution and are recommended for excipient applications, topical creams, lotions, personal care products, and solid oral dose.. See page 373,column B of Parveen for optimization of formulation properties of hydrophobic drug with PEGs. Also note that the lone instant is exemplified PEG3350 is commercially available OTC laxative with inherent muscle relaxant property of Dantrolene.
All the claimed elements active ingredient and excipients as defined are known in the prior art cited. Why and how of choosing different excipients by routine optimization is also taught in the prior art cited. As such nothing unobvious is seen in the claims.
Response to Remarks filed 08/12/202:
Applicants argument focus on the following:
D1, D2 and D3 do not teach the specific combination with respect to
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and the specific range of MW of PW as amended.
There is no reasonable expectation of success, because
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And
Brady is drawn to PEG solid dosage forms and the PEG is among many polymers and Brady is silent with regards to antifoaming use of PEG.
Why osa would combine Parveen with D1 is unclear.
Brewster does not remedy the deficiencies of, D1, D2, D3, Dhawan, Brady or Parveen, because it is invoked for use of modified cyclodextrins, rather than the claimed PEG molecular weight range.
Working Examples 3 and 4 formulations demonstrate the PEG unexpected property.
Applicants arguments are not persuasive. The PEG used in the pointed out Examples 3 and 4 is the specific PEG3350, commercially available and not Applicants discovery. See previous Office Action bottom of page 8.
The claim is not limited to this PEG3350. Note that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Further according to MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-10.2019], "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." In addition, the Example 4 is also limited with respect to the particle size of
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AND specific ratio of the (only) exemplified PEG to the
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and specific cyclocdextrin (and amount), made as per page 29 (above the pointed out Table 4).
As such the alleged unexpected property is the result of combination of multiple factors.
As noted in the previous action, the claims are drawn to selective combination of prior art elements.
Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). 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 was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office.
Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
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.
Previously presented rejection of claim(s) 1-4, 6-7, 9-11, 14, 17, 20 and 23-29 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11844782 further in view of Schwebel WO2017067980 (hereinafter Document D1 or D1); Haldar US2020179313 (hereinafter Document D2 or D2); Tong US 20200268705 (hereinafter Document D3 or D3); Dhawan, Pharmaceutical Technology MAY 2005 Vol: 29 Issue: 5, 72-80. Brewster, Pharmazie. 2002 Feb;57(2):94-101; Brady, Chapter 7 Developing Solid Oral Dosage Forms, Polymer Properties and Characterization, 2017 and Parveen, European Journal of Pharmacology 670 (2011) 372–383 is maintained for reasons of record.
Applicant arguments based on the idea that
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As explained under section, Claim Rejections - 35 USC § 103, Applicants arguments with respect to the cited references are not persuasive.
Previously presented rejection of claim(s) 1-4, 6-7, 9-11, 14, 17, 20 and 23-29 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of copending Application No. 18/503401 (reference application) further in view of Schwebel WO2017067980 (hereinafter Document D1 or D1); Haldar US2020179313 (hereinafter Document D2 or D2); Tong US 20200268705 (hereinafter Document D3 or D3); Dhawan, Pharmaceutical Technology MAY 2005 Vol: 29 Issue: 5, 72-80. Brewster, Pharmazie. 2002 Feb;57(2):94-101; Brady, Chapter 7 Developing Solid Oral Dosage Forms, Polymer Properties and Characterization, 2017 and Parveen, European Journal of Pharmacology 670 (2011) 372–383 is maintained for reasons of record.
Applicant arguments based on the idea that
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As explained under section, Claim Rejections - 35 USC § 103, Applicants arguments with respect to the cited references are not persuasive.
The following was previously presented for motivation part of TSM.
Feldman, Understanding ‘Evergreening’ : Making Minor Modifications Of Existing
Medications To Extend Protections, Health Affairs June 2022 41:6, 801-804
Dwivedi, Evergreening: A deceptive device in patent rights, Technology in Society 32, (2010) 324–330.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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.
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 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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
