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 Arguments
Applicant's arguments filed 06/12/2025 have been fully considered but they are not persuasive.
First, applicant argues that the studies of in vitro anti-GBM activity of BIM2b were performed only in ethanolic form. While acknowledged, the fact that there are no working examples of such does not invalidate the fact that the prior art is generally directed toward the use of BIM2b for treating GBM and that liposomal formulations of compounds of formula (I) are taught. This is sufficient to establish the use of BIM2b in liposomal form for treating GBM. Similarly, that the anti-tumor effect of BIM2b in liposomal form was only studied on extra-cranial cancer cells does not preclude their use on GBM cells.
It is acknowledged that a PHOSITA cannot predict, with certainty, in vivo results from in vitro results. However, the prior art clearly teaches that the compounds of the disclosure such as BIM2b are useful for treating GBM. Administering said compound in an alternative carrier has a reasonable expectation of success in view of said teachings. Changing the carrier cannot be considered to render the composition non-obvious absent unexpected results and/or a teaching away from doing so. The standard for obviousness is based upon a preponderance of the evidence and a reasonable expectation of success, both of which favor obviousness of the instant claims.
With respect to the in vivo data, the lack of direct or indirect comparison between the formulation of the prior art and the claimed formulation renders it impossible to determine whether the results are truly unexpected. It is unclear whether the results presented in the instant specification would have been achieved with the prior art formulation. Applicant is reminded that the claims must be commensurate in scope with any unexpected results.
Note that the Examiner has considered whether the prior art can be considered to teach away from alternative formulations, but while liposomal formulations are taught by the prior art, there does not appear to be any teaching that said formulation is necessary for the utility of the prior art compositions.
Additional arguments regarding solubility, oral administration, etc. have been addressed in previous Office Actions and are not addressed herein as they apply in equal or greater force to the instant claims.
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 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 25-33 and 36-46 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/168096, Savla et al., "Review and analysis of FDA approved drugs using lipid-based formulations" Drug Development and Industrial Pharmacy, 2017, Vol. 43, No. 11, 1743-1758, Kritchevsky et al. "Solubility of Cholesterol in Various Fats and Oils" Experimental Biology and Medicine, 1964, Vol. 116, No. 1, 104-107 and Jandacek et al., "Effect of an aqueous phase on the solubility of cholesterol in an oil phase" Journal of Lipid Research, 1977, Vol. 18, No. 2, 203-210.
Regarding claim 25, ‘096 teaches a method for treating a neoplastic pathology (“Compound of formula (I) … for use … in the treatment of glioblastoma multiforme,” claim 16) or a malignant haemopathy (“Compound of formula (I) … for use in the treatment of malignant haemopathies,” claim 18), comprising administering to a patient in need thereof an effective amount of a composition comprising at least one 7B-hydroxycholesterol derivative (claims 1, 16, 18) and a lipid vehicle (claims 9-14; pp. 9-14), wherein the 7B-hydroxycholesterol derivative corresponds to formula (I), including the instantly claimed elected species (claims 1, 6). The composition of ‘096 consists of a liposome (claim 10), or the compound is combined with phospholipids, in liposomal or non-liposomal form (claim 14). The composition of ‘096 is in a form suitable for oral administration (claims 12 and 13)).
‘096 does not teach the method wherein said lipid vehicle comprises an oil or a mixture of oils.
The skilled artisan would have found the instantly claimed method, wherein an oil or mixture of oils is used in lieu of phospholipids in liposomal or non-liposomal form, at least obvious to try. See MPEP 2143. The skilled artisan would have pursued the known potential solutions with a reasonable expectation of success.
Lipid-based drug delivery systems (LBDDS), which includes the phospholipid vehicle of the prior art composition, are well-known in the art for delivery of poorly soluble and/or poorly permeable drugs. The phospholipid formulation of the prior art is an example of an LBDDS, and the skilled artisan would have found it obvious to explore alternative LBDDS under routine optimization. Type I LBDDS comprise pure oils, limited or not dispersion, and require digestion (Savla, Table 2, pp. 1748).
Savla teaches:
“Early lipid formulated drugs contain almost exclusively oils. Ritonavir (NDA approval: 1996) was the first LBDDS formulated drug that did not contain oil (Table 1). The biggest advantage of using oil is that lipophilic drugs are solubilized and dissolution of the drug within the GI tract is not required. Once digested, there are higher odds that the drug will stay in solution due to the micellization process.” (Lipids, pp. 1644-1649).
Oil-based formulations of the lipophilic drug BIM2b would have been prima facie obvious. MPEP 2143. The advantages of oil-based delivery are clearly stated, and would have been favored for delivery of BIM2b. Further, given that the earliest LBDDS comprised oil-based delivery systems, there is a knowledge in the art that oil-based systems would be one of the default systems to try. This is further supported by the ease of implementing an oil-based LBDDS relative to other forms of LBDDS.
The argument that cholesterol has low solubility in oils is acknowledged; the solubility of cholesterol in various oils at 37C is <10% (Tepper, whole document, particularly Tables 1-3). However, the instantly claimed species, BIM2b, has a substantially different structure from cholesterol, and would not necessarily be expected to follow the same solubility patterns as cholesterol. BIM2b comprises 2 esters and a ketal moiety, which the skilled artisan would expect to increase solubility of the compound in oils, which contain triglycerides with multiple ester groups. Elemental analysis of BIM2b indicates 74.39% C, 9.85% H, and 16.76% O with a molecular weight of 572.83. Elemental analysis of cholesterol
indicates 83.87% C, 11.99% H, and 4.14% O with a molecular weight of 386.66. This indicates a 148% molecular weight and 404% oxygen content of BIM2b relative to cholesterol. While molecular weight and elemental analysis are reductive properties when attempting to compare certain properties of organic compounds such as solubility, they further demonstrate that BIM2b is a substantially different molecule from cholesterol, and the solubility of BIM2b in oil cannot be predicted to match that of cholesterol simply because it is a cholesterol derivative. Further, it is known in the art that esterification of cholesterol increases solubility in oil. Mattson teaches 23% solubility of cholesterol oleate in triolein at 21 C compared to 2.8% solubility of cholesterol in triolein at 21 C (Table 1, pp. 206). Accordingly, the skilled artisan would expect diesterification of a 7-betahydroxycholesterol to also increase solubility in oil. Thus, not only would the skilled artisan have found it obvious to try a solution comprising oil, but the skilled artisan would have had a reasonable expectation of success.
Further, the alleged advantages of 1) enabling the drug to cross the blood brain barrier and 2) stability in acidic/basic conditions are expected results. First, it is well known in the art that lipids such as triglycerides in oils enable crossing the BBB. Second, it is well-known in the art that triglycerides form micelles in aqueous solution. An oil solution of the instantly claimed compound would form micelles in the acidic environment of the stomach, protecting the compound from acidic or basic conditions present.
Regarding claim 26, ‘096 teaches the treatment of glioblastoma multiforme (claim 16).
Regarding claim 27, the composition of ‘096 is in a form suitable for oral administration (claims 12 and 13)).
Regarding claim 28, the Type I LBDDS taught by Savla are in solution (Lipids, pp. 1644-1649).
Regarding claim 29, the use of an oil-based LBDDS obviates the need for lipid vesicles formed from one or more lipid layer(s) or consisting of phospholipids in non-liposomal form.
Regarding claims 30-32, 41 and 43-46, Savla teaches the use of vegetable oils in LBDDS, including oils such as maize/corn oil (Table 1, pp. 1745-1747). Any other oils are taught by the prior art or can be considered obvious variants.
Regarding claim 33, Savla does not explicitly teach the use of argan oil. However, it is recognized in the art that vegetable oils have similar properties owing to their similar structures, only differing by fatty acid chain length/saturation. Further, the genus of readily, commercially available vegetable oils is small. The skilled artisan would seek optimal conditions under routine optimization by testing various common oils, such as argan oil, without undue burden, rendering the use of argan oil obvious.
Regarding claim 34-37 and 42, the compound BIM2b is taught by ‘096 (claim 6).
Regarding claims 38-40, ‘096 teaches liposomes containing 0.086 mg/mL and 0.133 mg/mL of BIM2b (2) Preparation of the liposomes, pp. 32-35). An example is also provided wherein the amount of active molecule with respect to the phospholipid can be approximately 15% (pp. 11). The skilled artisan would have found it obvious to modify these ranges dependent upon the solubility in the instantly claimed lipid vehicle.
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 25-33 and 36-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 10,800,806 in view of Savla et al., "Review and analysis of FDA approved drugs using lipid-based formulations" Drug Development and Industrial Pharmacy, 2017, Vol. 43, No. 11, 1743-1758, Kritchevsky et al. "Solubility of Cholesterol in Various Fats and Oils" Experimental Biology and Medicine, 1964, Vol. 116, No. 1, 104-107 and Jandacek et al., "Effect of an aqueous phase on the solubility of cholesterol in an oil phase" Journal of Lipid Research, 1977, Vol. 18, No. 2, 203-210.
As stated by applicant in the 07/05/2024 arguments, US ‘806 corresponds to WO ‘096, and therefore the arguments set forth above in connection with the prior art rejection and the prior art rejection itself apply with equal or greater force to the double patenting rejection.
Conclusion
Claims 25-33 and 36-46 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JED A KUCHARCZK whose telephone number is (571)270-5206. The examiner can normally be reached Mon-Fri 7:30 to 5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JED A KUCHARCZK/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623