DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Election/Restriction
In response to the Requirement for Restriction/Election, mailed on 21 February 2025, Applicant has cancelled claims 1-33 and added new claims 34-66.
Original claims 1-33 were drawn to three distinct inventions:
Group I, claims 1-20 and 26-33, drawn to a pharmaceutical formulation;
Group II, claims 21-24, drawn to a method of treatment; and
Group III, claim 25, drawn to a microneedle device.
New claims 34-63 are drawn to a method of treatment, corresponding to original Group II, claims 64-65 are drawn to a pharmaceutical formulation and kit, corresponding to original Group I, and claim 65 is drawn to a microneedle device, corresponding to original Group III.
The Applicant has elected the method of treatment, claims 34-63, with traverse in the reply filed on 21 August 2025. The traversal is on the ground that the “prospective species election [has] not…been made with respect to the new claims” (pg. 10, final para. of the remarks). This is not found persuasive because the Requirement for Restriction/Election, mailed on 21 February 2025, could not consider claims which had not yet been submitted.
The requirement is still deemed proper and is therefore made FINAL.
New claims 34-63 incorporate many of the limitations from claims 1-20 and 26-33, drawn to a pharmaceutical formulation. As a result, further species elections are required for new claims 34-63. During a telephone conversation with Bob Hodges on 30 October 2025, a provisional election was made with traverse to prosecute the invention of claims 34-63, and the following species:
the therapeutic agent is allopregnanolone;
the one or more lipophilic compounds are caprylic/capric mono- and diglycerides;
the solubilizer is 2-hydroxypropyl b-cyclodextrin;
the surfactant is sorbitan monooleate;
the co-surfactant is diethylene glycol monoethyl ether; and
the transdermal penetration enhancer is ethanol.
Affirmation of this election must be made by applicant in replying to this Office Action.
The requirement for species election of a route of administration is withdrawn.
Status of Claims
Claims 1-33 are cancelled.
New claims 34-66 are added.
Claims 34-66 are pending in the instant Office Action.
Claims 64-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 21 August 2025.
Claims 34-63 are under consideration in the instant Office Action, to the extent of the following elected species:
the therapeutic agent is allopregnanolone;
the one or more lipophilic compounds are caprylic/capric mono- and diglycerides;
the solubilizer is 2-hydroxypropyl b-cyclodextrin;
the surfactant is sorbitan monooleate;
the co-surfactant is diethylene glycol monoethyl ether; and
the transdermal penetration enhancer is ethanol.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 15 May 2023, and 8 June 2023, were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner, except for Kovacevic et al. (Int. J. Pharmaceut. 2011, 406 (1-2), 136.), which was submitted with only the abstract.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in line 29 of pg. 1. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Objection to the title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The title of the instant application is “TOPICAL NEUROSTEROID FORMULATIONS”. The title should be brief but technically accurate and descriptive and should contain fewer than 500 characters. The title does not reflect the main inventive concept of Applicant’s invention and the major components of the invention. The title is generic and can be applicable to any “TOPICAL NEUROSTEROID FORMULATIONS”. The Examiner advises Applicant to consider including major components of the composition, primary purpose of the invention, and/or the general steps taken to achieve the claimed invention in the title to precisely reflect the inventive concept. Inasmuch as the words "new," "improved," "improvement of," and "improvement in" are not considered as part of the title of an invention, these words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. Similarly, the articles "a," "an," and "the" should not be included as the first words of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues.
Claim Objections
Claim 36 is objected to because of the following informality: Lines 1-2 of claim 36 recite “the pharmaceutically acceptable carrier comprising water…” (bold added for emphasis). The bolded word should end with “es” instead of “ing”, instead reciting “the pharmaceutically acceptable carrier comprises water…” (bold added for emphasis).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 49, 55, and 59 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 49 recites “a delivery vehicle selected from the group consisting of intravenous…” (bold added for emphasis). Intravenous delivery is a route of administration, rather than a delivery vehicle, and its inclusion in a group of delivery vehicles is therefore indefinite.
Claim 55 recites “the one or more lipophilic compounds originally belonged to the oil” in lines 1-2. The meaning of this limitation is unclear and the instant specification does not provide a definition of the phrase, rendering the claim indefinite.
Claim 59 recites “at a weight ratio of about 1” in line 2. It is unclear if the weight ratio is between the surfactant and one other component of the pharmaceutically acceptable carrier, between the surfactant and all other components of the pharmaceutically acceptable carrier, between sorbitan monooleate and polysorbate 80 when both species are surfactants, or some combination of the aforementioned. This rejection may be overcome by amending the claim to recite a relationship governed by the ratio of “about 1”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 34-35 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brinton et al. (U.S. Patent Application Publication No. US 2017/0258810 A1, published on 14 September 2017, hereafter referred to as Brinton).
Brinton teaches methods of reversing or preventing neurological disease or defects associated with neural loss or degeneration via administration of compositions containing 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) (Abstract and para. [0002]). The method for treating or preventing neurological deficits due to neurodegenerative disease, such as Parkinson’s disease (para. [0010] and claim 22), is taught to comprise administration of a composition comprising allopregnanolone (claim 1). This method of treating or preventing neurological deficits due to a disease that may be Parkinson’s disease is considered analogous to the method “for treating or preventing neuronal damage caused by Parkinson’s disease” recited in instant claim 34 and therefore claims 34 and 44 are anticipated by Brinton. In addition, the method is taught to be administered via a route which may be transdermal, injection (subcutaneous or intravenous), or pulmonary, which anticipates instant claim 35.
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 34-49 and 51-63 are rejected under 35 U.S.C. 103 as being unpatentable over Brinton (U.S. Patent Application Publication No. US 2017/0258810 A1, published on 14 September 2017) in view of Sintov et al. (J. Controlled Release 2010, 148, 168., provided by Applicant in the IDS filed on 13 May 2023, hereafter referred to as Sintov), Yao et al. (J. Exp. Med. 2012, 209 (13), 2501., hereafter referred to as Yao), and Prajapati et al. (Pharm. Res. 2012, 29, 285., hereafter referred to as Prajapati).
Brinton teaches methods of reversing or preventing neurological disease or defects associated with neural loss or degeneration via administration of compositions containing 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) (Abstract and para. [0002]). The method for treating or preventing neurological deficits due to neurodegenerative disease, such as Parkinson’s disease (para. [0010] and claim 22), is taught to comprise administration of a composition comprising allopregnanolone (claim 1). This method of treating or preventing neurological deficits due to a disease that may be Parkinson’s disease is considered analogous to the method “for treating or preventing neuronal damage caused by Parkinson’s disease” recited in instant claim 34. The composition is further taught to comprise a dextrin (claim 2), ethanol (claim 7), diglycol monoethyl ether (para. [0082]), which is interpreted as equivalent to the elected diethylene glycol monoethyl ether, and sorbitan monooleate (para. [0084]). The composition is taught to be capable of being formed as a stable microemulsion (para. [0095]) and is taught to have a carrier, in which the API is dissolved (para. [0062-0063]) at an amount from 0.5-100% w/w of the composition (para. [0074]). Further, Brinton teaches that their composition may comprise the lipophilic compounds capric/caprylic triglycerides and that the method may be administered via a route which may be transdermal, injection (subcutaneous or intravenous), or pulmonary (claim 1).
Allopregnanolone is taught to be administered “at dosages and for periods of time effective to stimulate or induce neural proliferation and/or to protect against neural loss in an individual” (para. [0052]). Brinton teaches that this may be achieved by administering the composition comprising allopregnanolone in a single dose or over several doses, with the several doses being administered daily, every other day, weekly, or monthly (para. [0012]). When administered using multiple doses, the range of API is taught to be about 0.1-1,000 mg, but the dose and administration frequency can be “readily determined by the treating physician” (para. [0052]). The time period of administration is taught to range from one month to 72 weeks (para. [0012] and claims 16-18). The instant specification does not define the manner in which the formulation comprising allopregnanolone “provides a dose of 4 mg” and it is therefore interpreted as being administered at a concentration of 4 mg allopregnanolone, which falls within the range taught by Brinton.
Guidelines on the obviousness of similar and overlapping ranges, amounts, and proportions are provided in MPEP § 2144.05. With respect to claimed ranges which “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). These guidelines apply to the dose of allopregnanolone recited in instant claims 37, 39-43, and 45-48 and the frequency of administration recited in instant claims 39-42 and 45-48. The teachings of Brinton encompass the claimed dose of 4 mg and the frequency of once weekly administration over the time span of 12 weeks or 3 months, rendering them obvious.
Brinton does not teach the quantity of the surfactant and co-surfactant, the dextrin to be 2-hydroxypropyl b-cyclodextrin, nor the lipophilic compounds caprylic/capric mono- and diglycerides. These deficiencies are offset by the teachings of Sintov, Yao, and Prajapati.
Sintov teaches the development and performance of a new microemulsion nasal spray (Abstract). Microemulsions are taught to have improved absorption of low-molecular-weight drugs following nasal administration, but the mechanism is poorly understood (pg. 169, left column, para. 1). Sintov hypothesized that a non-irritating microemulsion system is the source of this desirable effect and studied the impact of different microemulsion systems on nasal sprays containing lispro insulin (pg. 169, left column, para. 2).
In Figure 1, Sintov demonstrated that in microemulsions comprising more than 10% w/w oil, the maximum water solubilization capacity was 50% w/w, and that the optimally stable co-surfactant: surfactant ratio was 1:5 (pg. 171, 3.1. Characterization of the microemulsion system). Analysis of Fig. 1 demonstrates that that the microemulsion remains stable across a surfactant/co-surfactant weight percentage range, from as low as ~50% w/w of the surfactant/co-surfactant-water-oil mixture to as high as ~90% w/w, and that an optimal ratio contains ~87% w/w of the surfactant/co-surfactant mixture (pg. 172, left column, para. 2 - pg. 173, left column, para. 2).
Guidelines on the obviousness of similar and overlapping ranges, amounts, and proportions are provided in MPEP § 2144.05. With respect to claimed ranges which “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). These guidelines apply to the quantity of surfactant and co-surfactant in instant claim 36. The teachings of Sintov significantly overlap with the claimed range, rendering it obvious.
Yao teaches the neuroprotective properties of cyclodextrins in cells and mouse models (Abstract). Cyclodextrins, cyclic polysaccharide compounds, are taught to extract cholesterol from cultured cells (pg. 2502, right column, para. 1). Cholesterol plays an important role in neurodegenerative diseases, for example increasing the risk factors of Alzheimer Disease when present in high concentrations, and the ability of cyclodextrins to regulate cholesterol has been observed to correct “abnormal cholesterol metabolism, and [prevent] neurodegenerative changes” in mice models of the lipid storage disease Niemann-Pick type C1 (pg. 2501, left column, para. 1 - pg. 2503, left column, para. 1).
Hydroxypropyl b-cyclodextrin (HP-b-CD) was administered to mice models which overexpress human amyloid precursor protein (APP), a protein associated with neurons (pg. 2503, left column, para. 2), and found to “enhance cholesterol efflux through increased expression of cholesterol transporters” (pg. 2509, left column, penultimate para.). Further, administration of HP-b-CD was observed to significantly increase expression of ABCA1, which reduces amyloid deposition, and to decrease deposition of plaques in the brains of the mouse models (pg. 2509, right column, para. 1). Yao concludes that administration of HP-b-CD “significantly improved memory deficits and reduced amyloid deposition” and could have therapeutic potential in the treatment of neurodegenerative diseases such as Alzheimer Disease (pg. 2509, right column, final para.).
Prajapati teaches a comparative evaluation of mono-, di-, and triglycerides for applications in pharmaceutical dosage formulations (Title and Abstract). Medium chain lipids are taught to be popular in drug formulations due to being liquid at room temperature and their ability to exist in different phases when mixed with water (pg. 299, left column). When using Capmul® MCM EP, a mixture of 60% caprylic/capric monoglycerides and 35% caprylic/capric diglycerides, Prajapati found that, when used in combination with a surfactant and water, the mono- and diglyceride mixture was capable of forming microemulsions and did not form a gel phase, which may be desirable as the gel may trap the API in the formulation, thereby delaying or impeding its release (pg. 292-293, Effect of Monoglyceride/Diglyceride Combination). Further, the mixture can be optimized to suit desired formulation characteristics by adjusting component ratios according to the phase diagram in Fig. 4 and data in Table III (pg. 293, Effect of Monoglyceride/Diglyceride Combination). Prajapati concludes that, for many lipid/surfactant mixtures, undesirable gel or liquid crystalline phases can be produced, but are “practically eliminated” when combining “monoglyceride with diglyceride or triglyceride at 1:1 ratios” (pg. 304, Conclusion).
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 combine the teachings of Sintov, Yao, and Prajapati with the method of Brinton to arrive at the method of claims 34-49 and 51-63 because combining or substituting elements known in the prior art in related methods produces predictable results. Brinton teaches a method of treating, reversing, or preventing neurological disease or defects associated with neurodegenerative disease, such as Parkinson’s disease, comprising administration of a composition comprising allopregnanolone at doses and frequencies that render obvious those recited in instant claims 37, 39-43, and 45-48. Brinton further taught their composition to comprise a dextrin, ethanol diglycol monoethyl, capric/caprylic triglycerides, and sorbitan monooleate, to be in the form of a stable microemulsion, and to contain the API in a carrier at an amount from 0.5-100% w/w of the composition.
In view of the teachings of Sintov, a person of ordinary skill would be motivated to make the quantity of surfactant and co-surfactant in their composition be ~50-90% w/w because Brinton does not teach a quantity of surfactant and/or surfactant+co-surfactant to use and the teachings of Sintov provide missing information an ordinary artisan would need to practice the complete method of Brinton. In addition, Sintov teaches the above range to produce a stable microemulsion, which would be desirable to an artisan utilizing the above composition in a method of treatment.
In view of the teachings of Yao, one of ordinary skill would be motivated select 2-hydroxypropyl b-cyclodextrin as the dextrin to use in the composition taught by Brinton because Yao teaches the particular molecule to have use in neuroprotection, which the ordinary artisan would desire in the method taught by Brinton of treating, reversing, or preventing neurological disease or defects associated with neurodegenerative disease. Further, Brinton teaches the genus of dextrin, but does not teach a specific dextrin, and the teachings of Yao would provide missing information and allow the ordinary artisan to practice the complete method of Brinton.
Finally, in view of the teachings of Prajapati, a person of ordinary skill would be motivated to use caprylic/capric mono- and diglycerides from Capmul® MCM EP in the composition administered as part of the method of Brinton because Prajapati teaches the mixture, when used alongside a surfactant and co-surfactant, was capable of forming a stable microemulsion without forming an undesirable gel. Brinton and Sintov both taught the utility of forming compositions as microemulsions and the ordinary artisan would desire the use of components that further aid the stability of the compositions.
Instant claims 40, 42, 46, and 48 recite the method of administration of a composition comprising allopregnanolone “improves one or more motor skills in the subject” and instant claim 51 recites the solubility of allopregnanolone to be higher in the presence of caprylic/capric mono- and diglycerides, 2-hydroxypropyl b-cyclodextrin, sorbitan monooleate, and diethylene glycol monoethyl ether than in the absence of those components. The teachings of Brinton, Sintov, Yao, and Prajapati have rendered obvious a method of treating Parkinson’s’ disease comprising administering a composition comprising allopregnanolone, caprylic/capric mono- and diglycerides, sorbitan monooleate, ethanol, and diethylene glycol monoethyl ether in the quantities recited and with the frequency recite (vide supra). Brinton, Sintov, Yao, and Prajapati are silent regarding the motor skills of subjects following administration of the above method and the solubility of allopregnanolone.
"[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945).
Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195. Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531, 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511-96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). See MPEP § 2112.
In Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), Persion contended that the district court erred in applying the inherency doctrine in its obviousness analysis because prior art reference Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581); Reply Br. 19.
To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to the court’s prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607, 610. In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
Because the teachings of Brinton, Sintov, Yao, and Prajapati render obvious a method that comprises administration of a composition comprising allopregnanolone, at the dosage recited in claim 37, caprylic/capric mono- and diglycerides, 2-hydroxypropyl b-cyclodextrin, sorbitan monooleate, and diethylene glycol monoethyl ether, over the time period and frequencies as instant claims 37, 39-43, and 45-48, the composition would necessarily also improve “one or more motor skill in the subject” and instant claims 40, 42, 46, and 48 are also rendered obvious. Further, the solubility of allopregnanolone is an inherent property of the molecule, and its presence in the composition rendered obvious above would have the same solubility properties as recited in instant claim 51. As a result, there is a reasonable expectation of success in arriving at the method of instant claims 34-49 and 51-63 in view of the teachings of Brinton, Sintov, Yao, and Prajapati.
Claims 34 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Brinton (U.S. Patent Application Publication No. US 2017/0258810 A1, published on 14 September 2017) in view of Henry et al. (Proceedings MEMS 98. IEEE. Eleventh Annual International Workshop on Micro Electro Mechanical Systems., 1998, 494., provided by Applicant in the IDS filed on 15 May 2023, hereafter referred to as Henry).
Brinton teaches the above and particularly relevant claim 50 teaches that their method may administer the composition comprising allopregnanolone intravenously.
Brinton does not teach their method to administer their composition using a microneedle device. This deficiency is offset by the teachings of Henry.
Henry teaches the utility of microneedle devices in the transdermal delivery of drugs (Abstract). Transdermal delivery of drugs is taught to overcome limitations due to the size, charge, and sensitivity of drugs as well as limitations from other methods of administration such as GI tract degradation of orally administered drugs (pg. 1, left column, final para. - right column, para. 1). However, human skin poses “an extremely good barrier to most drugs, resulting in low drug delivery rates that are not therapeutically effective” (pg. 1, right column, para. 1). Using a microneedle device, Henry administered drugs across the skin barrier “without causing any pain” (pg. 1, right column, final para.). Henry concluded that microneedles are simple to produce, suitable for many applications, capable of “increasing skin permeability by up to more than four orders of magnitude”, and have “the potential to significantly increase the number and type of drugs which can be delivered across the skin” (pg. 5, left column, Conclusions).
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 utilize microneedles to practice the method of Brinton in view of the teachings of Henry because using a known device to apply a known technique yields predictable results. Brinton anticipated a method of treating, reversing, or preventing neurological disease or defects associated with neurodegenerative disease, such as Parkinson’s disease, comprising administration of a composition comprising allopregnanolone at doses and frequencies that anticipate those recited in instant claims 43-49. In view of the teachings of Henry, one of ordinary skill would be motivated to use a microneedle to administer the composition taught in the method of Brinton because Henry teaches this administration method to cross the skin barrier without inducing pain and increase the API skin permeability, which the ordinary artisan would desire in a method that requires the delivery of an API to a user. As a result, there is a reasonable expectation of success in arriving at the method of claim 50 in view of the teachings of Brinton and Henry.
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 34-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 10-12, 15-20, and 22 of U.S. Patent No. 11,207,331 B2 in view of Sintov (J. Controlled Release 2010, 148, 168., provided by Applicant in the IDS filed on 13 May 2023), Gupta et al. (Sci. Pharm. 2012, 80 (4), 1061., hereafter referred to as Gupta), Yao (J. Exp. Med. 2012, 209 (13), 2501.), Prajapati (Pharm. Res. 2012, 29, 285.), and Henry (Proceedings MEMS 98. IEEE. Eleventh Annual International Workshop on Micro Electro Mechanical Systems., 1998, 494.).
Commonly assigned U.S. Patent No. 11,207,331 B2 recites a method of treating or preventing neurological deficits in a person suffering from a neurodegenerative disease, which in one embodiment is Parkinson’s disease, comprising the administration of a composition comprising allopregnanolone (claims 11-12, 15, and 22). The route of administration in the method is recited to be transdermal, injection, or pulmonary (claim 1) and may be administered weekly or less frequently over a span of time from 1-6 months (claims 16-19). The composition is further recited to comprise a dextrin, ethanol, and diglycol monoethyl ether (claims 2-3, 7, and 10). Finally, ‘331 recites the dose of allopregnanolone to be from 0.1-100 mg (claim 20).
Commonly assigned U.S. Patent ‘331 does not recite the composition of their method to comprise caprylic/capric mono- and diglycerides or sorbitan monooleate, the dextrin to be 2-hydroxypropyl b-cyclodextrin, the weight percent of the surfactant/co-surfactant, nor the composition to be administered via microneedle. These deficiencies are offset by the teachings of Sintov, Gupta, Yao, Prajapati, and Henry.
Sintov, Yao, Prajapati, and Henry have been described above.
Gupta teaches formulations for overcoming solubility issues with the drug sertraline for transdermal delivery (Abstract). To deliver sertraline across the skin barrier, Gupta employed transfersomes, metastable vesicles that can “squeeze” through pores in the skin and non-invasively deliver the API (pg. 1062, para. (2-4). The study sought to optimize the formulation for in vitro release and utilized the non-ionic surfactant Span® 80, which is a trade name for sorbitan monooleate, as evidenced by the instant specification (Abstract and pg. 1063, para. 1). Span® 80 is taught to be biocompatible, pharmaceutically acceptable, and capable of efficiently entrapping the API and excipients in vesicles (pg. 1067, para. 4-6). Gupta concluded that the vesicle comprising sorbitan monooleate possessed “excellent release and permeation” properties, did not irritate subject skin following administration, and could be a promising carrier for a variety of APIs (pg. 1077, Conclusion).
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 combine the teachings of Sintov, Gupta, Yao, Prajapati, and Henry with the method recited in U.S. Patent ‘331 to arrive at the claimed invention because combining prior art elements from related inventions to impart known benefits yields predictable results. Commonly assigned patent ‘331 recites a method for treating or preventing neurological deficits from neurodegenerative disease, which in one embodiment is Parkinson’s disease, comprising the administration of a composition comprising allopregnanolone in the amount and frequency recited in the instant application. The route of administration in the method is recited to be transdermal, injection, or pulmonary, and the composition is recited to comprise a dextrin, ethanol, and diglycol monoethyl ether.
In view of the teachings of Sintov, a person of ordinary skill would be motivated to add a surfactant and co-surfactant to their composition in the amount of ~50-90% w/w because Patent ‘331 does not recite the inclusion of nor a quantity of surfactant and/or surfactant+co-surfactant to use and Sintov teaches the above range to produce a stable microemulsion, which would be desirable to an artisan utilizing the above composition in a method of treatment. In view of the teachings of Gupta, an ordinary artisan would be motivated to select the surfactant sorbitan monooleate because Gupta teaches the surfactant to provide a stable vesicle for delivering APIs, to be biocompatible and pharmaceutically acceptable, and to produce no skin irritation to users following administration.
In view of the teachings of Yao, one of ordinary skill would be motivated select 2-hydroxypropyl b-cyclodextrin as the dextrin to use in the composition recited in ‘331 because Yao teaches the particular molecule to have use in neuroprotection, which the ordinary artisan would desire in the method recited by commonly assigned patent ‘331 of treating or preventing neurological disease or defects associated with neurodegenerative disease. Further, ‘331 recites the genus of dextrin, but does not teach a specific dextrin, and the teachings of Yao would provide missing information and allow the ordinary artisan to practice the complete method of ‘331.
In view of the teachings of Prajapati, a person of ordinary skill would be motivated to use caprylic/capric mono- and diglycerides from Capmul® MCM EP in the composition administered as part of the method of ‘331 because Prajapati teaches the mixture, when used alongside a surfactant and co-surfactant, was capable of forming a stable microemulsion without forming an undesirable gel. Sintov taught the utility of forming compositions as microemulsions and the ordinary artisan would desire the use of components that further aid the stability of the compositions. Finally, in view of the teachings of Henry, one of ordinary skill would be motivated to use a microneedle to administer the composition recited in the method of ‘331 because Henry teaches this administration method to cross the skin barrier without inducing pain and increase the API skin permeability, which the ordinary artisan would desire in a method that requires the delivery of an API to a user.
Instant claims 40, 42, 46, and 48 recite the method of administration of a composition comprising allopregnanolone “improves one or more motor skills in the subject” and instant claim 51 recites the solubility of allopregnanolone to be higher in the presence of caprylic/capric mono- and diglycerides, sorbitan monooleate, and diethylene glycol monoethyl ether than in the absence of those components.
Instant claims 40, 42, 46, and 48 recite the method of administration of a composition comprising allopregnanolone “improves one or more motor skills in the subject” and instant claim 51 recites the solubility of allopregnanolone to be higher in the presence of caprylic/capric mono- and diglycerides, 2-hydroxypropyl b-cyclodextrin, sorbitan monooleate, and diethylene glycol monoethyl ether than in the absence of those components. The teachings of Brinton, Sintov, Yao, and Prajapati have rendered obvious a method of treating Parkinson’s’ disease comprising administering a composition comprising allopregnanolone, caprylic/capric mono- and diglycerides, sorbitan monooleate, ethanol, and diethylene glycol monoethyl ether in the quantities recited and with the frequency recite (vide supra). Brinton, Sintov, Yao, and Prajapati are silent regarding the motor skills of subjects following administration of the above method and the solubility of allopregnanolone.
"[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945).
Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195. Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531, 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511-96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212, 214, 26 C.C.P.A. 937, 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). See MPEP § 2112.
In Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), Persion contended that the district court erred in applying the inherency doctrine in its obviousness analysis because prior art reference Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581); Reply Br. 19.
To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to the court’s prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607, 610. In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
Because the method recited by ‘331 and the teachings of Sintov, Gupta, Yao, and Prajapati render obvious a method that comprises administration of a composition comprising allopregnanolone, at the dosage recited in claim 37, caprylic/capric mono- and diglycerides, 2-hydroxypropyl b-cyclodextrin, sorbitan monooleate, and diethylene glycol monoethyl ether, over the time period and frequencies as instant claims 37, 39-43, and 45-48, the composition would necessarily also improve “one or more motor skill in the subject” and instant claims 40, 42, 46, and 48 are also rendered obvious. Further, the solubility of allopregnanolone is an inherent property of the molecule, and its presence in the composition rendered obvious above would have the same solubility properties as recited in instant claim 51. As a result, there is a reasonable expectation of success in arriving at the method of instant claims 34-63 in view of the method recited in commonly assigned U.S. Patent No. 11,207,331 B2 and in view of the teachings of Brinton, Gupta, Sintov, Yao, and Prajapati.
Claims 34-63 are directed to an invention not patentably distinct from claims 1-3, 7, 10-12, 15-20, and 22 of commonly assigned U.S. Patent No. 11,207,331 B2 in view of Sintov, Gupta, Yao, Prajapati, and Henry. Specifically, see above.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned U.S. Patent No. 11,207,331 B2, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Conclusion
No claims are allowed.
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