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 .
Application Status
The preliminary amendment filed on 9/23/2024 is acknowledged. Claims 1-15 and 17-21 are currently pending and under consideration
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements filed on 9/23/2024 and 4/29/2025 are acknowledged and have been considered except where lined through.
Drawings
The drawings are objected to because the annotations on the figures are difficult to read. . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The amendment to the specification filed on 9/23/2024 is acknowledged. However, while a clean copy has been included, there does not appear to be a “marked-up” copy of the specification.
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.
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.
Claim(s) 1-15, 17 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over LG Life Sciences (WO2006090997A1, 2006-08-31) referred to herein as LG in view of Oh NS Ignatious (US20060222694A1, 2006-10-05) and Baheti et al. (J. Excipients and Food Chem. 2010; 1 (1): 41-54).
LG teach isooxazoline derivatives having the cyclic acid hemiketal moiety of formula (1):
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for use as a caspase inhibitor, a process of preparing it and a pharmaceutical composition comprising it (abstract). With regards to the caspase inhibitor, LG teachs a compound having the formula
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,wherein R1 is an isoquinolinyl and R2 is an isopropyl which appears to be identical to the compound claimed in the instant application (see Example 2). With regards to the pharmaceutical composition, LG teaches that the compound of formula I is formulated as a parental injection, or percutaneous or oral depending on it application, wherein it is especially advantageous to formulate the composition in a unit dosage form for ease of administration and uniformity of dosage (paragraph 0188). Regarding the parental preparation, LG teaches that sterile water is typically used as the carrier, but other solvents such as Ringer’s fluid or isotonic NaCl solutions can be used for injection (paragraph 190). Moreover, LG teaches that the compounds of formula 1 can be used to treat a variety of diseases including, but not limited to, dementia, hepatitis, AIDS, sepsis, rheumatoid arthritis or ischemic cardiac diseases (paragraph 186). For example, LG teaches treatment of LPS-induced acute hepatitis in mice, wherein the compound, dissolved in a mixture consisting of PEF400:ethanol:Tween80 diluted with saline, is injected into the mouse (See Experimental Example 2, page 22).
While LG teaches a pharmaceutical composition comprising the compound of formula 1, LG does not specifically teach the process as claimed wherein formula I is dissolved in a solvent containing sugar to prepare a first solution, preparing a fist formulation in powder form by freeze-drying the first solution and preparing a second formulation that is a reconstitution solution containing a phosphate buffer, a surfactant, a pH adjusting agent or a combination thereof.
Oh and Ignatious teach topotecan liposomal compositions which can be reconstituted from a lyophilized form to an injectable liposome injection (abstract). In particular, Oh and Ignatious teach that one of the problems with topotecan is that it is susceptible, in aqueous environments, to hydrolysis at the alpha-hydroxy lactone ring, wherein the lactone ring opens to the carboxylate form which can be reduced if the compound is maintained in a low pH environment (paragraph 0006).
Baheti et al. teach that about 67% of lyophilized marketed preparations of small molecules contain excipients in their formulation, wherein the distribution of commonly used excipients of commonly used excipients in marketed lyophilized formulations of small molecules is shown by this pie chart
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(page 43, Figure 4). Moreover, Baheti et al. teach that the classification of commonly used excipients used in lyophilization of small molecules is as follows:
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(page 46, Figure 5). With regards to the bulking agents, Baheti et al. teach that bulking agents form the bulk of the lyophilized product and provide an adequate structure to the cake, wherein the structure of the lyophilized cake is important since proper cake formation leads to proper pore formation that provides the means for vapor to escape from the product during the drying cycle (page 43, 2nd column). Moreover, Baheti et al. teach that mannitol and glycine, are the most commonly used bulking agents, followed by, glucose, sucrose, lactose, trehalose and dextran and that the nature of the cake depends on the ratio of drug and bulking agent, showing an increases crystallization with an increase in amount of bulking agent(page 46, 1st column and page 49, 1st column, 2nd full paragraph). With regards to the buffering agent, Baheti et al. teach that the control of pH is critical to avoid degradation of the drug during processing, storage and reconstitution, thereby necessitating addition of buffering agent in the lyophilized formulation (page 49, 2nd column, 1st full paragraph). Regarding the surfactant, Baheti et al. teach that surfactants may be added at low levels to aid in the reconstitution of the drug if the drug does not show good wetting behavior (page 51, 2nd column). With regards to the co-solvent, Baheti et al. teach that water is the most commonly used solvent for lyophilization, but organic solvents are sometimes used to increase the primary drying rate, improve product stability, decrease reconstitution time by improving drug wettability or solubility, and also enhance the sterility assurance of the sample solution, wherein tert-butyl alcohol has been used to speed up the lyophilization process (page 51, 2nd column). Lastly, Baheti et al. teach some commercially available lyophilized small molecules such as topotecan which contains the excipients mannitol and tartaric acid (see page 45, Table 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the pharmaceutical composition taught by LG so as to form a lyophilized product including an excipient such as mannitol and/or tartaric acid at a low pHin view of the teachings of Oh and Ignatious and Baheti et al.. One would have been motivate to make such a medication, with a reasonable expectation of success, because:
Oh and Ignatious discuss the susceptibility of alpha-hydroxy lactone rings which can be reduced if the compound is maintained at a low pH; and
Baheti et al. teach that topotecan, another compound possessing an alpha-hydroxy lactone ring is sold as a lyophilized product containing mannitol and tartaric acid.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the excipients such as pH modifier, co-solvent, and surfactant of the lyophilized product in view of the teachings of Baheti et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Baheti et al. teaches the importance of excipients including bulking agents in the lyophilization process.
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)
Regarding the two step process and reconstitution liquid, this appears to be changing the sequence of adding ingredients, wherein the excipients are added after the lyophilization in the reconstitution liquid vs. added during the lyophilization step. It is noted that the specification does not appear to show any examples or comparisons of the excipients added during the lyophilization vs. after. See MPEP 2144.04 IV (C)
Claim(s) 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over LG Life Sciences (WO2006090997A1, 2006-08-31) referred to herein as LG in view of Oh NS Ignatious (US20060222694A1, 2006-10-05) and Baheti et al. (J. Excipients and Food Chem. 2010; 1 (1): 41-54), as applied above to claims 1-15, 17 and 20-21, in further view of D’Lima et al. (Athritis & Rheumatism 2006; 54(6): 1814-1821).
The combination of LG, Oh and Ignatious and Baheti et al. have been described above and incorporated herein. In short, the combination teaches a lyophilized preparation containing a compound of formula I in mannitol, wherein the lyophilized preparation is used in a method of treating a variety of diseases including, but not limited to, dementia, hepatitis, AIDS, sepsis, rheumatoid arthritis or ischemic cardiac diseases. In addition to these diseases, LG teaches that caspase inhibitors, such as
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, are known in the art to be useful for treating or alleviating osteoarthritis (paragraphs 9-10).
The combination does not specifically teach treating osteoarthritis, wherein the composition is administered within the joint cavity.
D’Lima et al. teach that caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis (Title). Specifically, D’Lima et al. teach that rabbits were treated with intraarticular (IA) injections of caspase inhibitors 3 times per week (see Methods).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by the combination to treat osteoarthritis via intraarticular injection (e.g. injection into the joint cavity) in view of the teachings of D’Lima et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-D’Lima et al. teach that caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis, wherein rabbits were treated with intraarticular (IA) injections of caspase inhibitors 3 times per week.
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.
At least claims 1, 9, 15 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1, 10 and 19 of copending Application No. 18/839,166 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the pharmaceutical formulation, method of making said formulation and method of treatment claimed in the reference application overlap in scope with the instantly claimed formulation, method of making and treatment claimed in the instant Application. In the instant case, the claims differ in that the reference application includes excipients with the lyophilization formulation, whereas in the instant application the excipients are present in the reconstitution liquid (note: cyclodextrin is a sugar). As such, this appears to be changing the sequence of adding ingredients, wherein the excipients are added after the lyophilization in the reconstitution liquid vs. contained within the lyophilization step. It is noted that the specification does not appear to show any examples or comparisons of the excipients added during the lyophilization vs. after. See MPEP 2144.04 IV (C)
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
Prosecution Insights