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 .
Priority
Examiner acknowledges that, according to the Filing receipt received 01/14/2026, that the instant application 18/872,223 filed 12/05/2024 is a 371 of PCT/EP2023/066146 filed 06/15/2023, which claims foreign priority of EPO application EP22179225.2 filed 06/15/2022. As such all of the instant claims have been awarded the effective filing date of 06/15/2022.
Information Disclosure Statement
The Information Disclosure Statement filed on 12/05/2024 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Claim Objections
Claim 6 is objected to because of the following informalities: Claim 6 does not end in a period. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10-13 and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating a neurodegenerative disease or disorder selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, neuroleptic malignant syndrome, dystonia, and schizophrenia, does not reasonably provide enablement for treating, preventing, or curing neurodegenerative diseases or disorders generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988); Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed.
The nature of the instant invention has claims which embrace prodrugs of apomorphine and their use in treating neurodegenerative disorders. While apomorphine is a known anti-Parkinsonian drug, there is no evidence that it would be effective in treating each and every neurodegenerative disease or disorder, let alone curing or preventing them (see definition of “treating” on pages 20-21 of the specification, bridging paragraph). In fact, none of these diseases or disorders have the expectation of being curable or preventable.
The treatment of neurodegenerative disorders generally cannot possibly be considered enabled.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
The scope of "neurodegenerative disorder" cannot be deemed enabled. The term "neurodegenerative disorder" covers a broad array of different disorders that have different modes of action and different origins. The term covers such diverse disorders as Alzheimer's Disease; Parkinson's Disease; ALS and variants such as forms of ALS-PDC; Gerstmann-Straussler-Scheinker Disease (GSS); Pick's Disease; Diffuse Lewy Body Disease; Hallervordon-Spatz disease; progressive familiar myoclonic epilepsy; Corticodentatonigral degeneration; progressive supranuclear palsy (Steele-Richardson-Olszewski); Huntington's disease; more than a dozen dementias collectively called "frontotemporal dementia and Parkinsonism linked to chromosome 17" (FTDP-17); Tourette's syndrome; Shy-Drager syndrome; Friedrich's ataxia and other spinocerebellar degenerations; Olivopontocerebellar atrophy (OPCA); spasmotic torticollis; Striatonigral degeneration; various types of torsion dystonia; certain spinal muscular atrophies, such as Werdnig-Hoffmann and Wohlfart-Kugelberg-Welander; Hereditary spastic paraplegia, Primary lateral sclerosis; peroneal muscular atrophy (Charcot-Marie-Tooth); Creutzfeldt-Jakob Disease (CJD); Hypertrophic interstitial polyneuropathy (Dejerine-Sottas); retinitis pigmentosa; Leber's Disease; and Hypertrophic interstitial polyneuropathy. These exhibit a very broad range of effects and origins.
For example, some give progressive dementia without other prominent neurological signs, such as Alzheimer's disease, whereas other dementias have such signs, such as Diffuse Lewy Body Disease. Some give muscular wasting without sensory changes, e.g., ALS, and some do have the sensory changes such as Werdnig-Hoffmann. Some are abnormalities of posture, movement or speech, such as Striatonigral degeneration, and other are progressive ataxias, such as OPCA. Some are linked to tau mutations, such as Alzheimer's disease and FTDP-17, and other such as Parkinson's clearly do not. Some affect only vision such as retinitis pigmentosa. Even within those that fall into the same category of effects, there are often striking differences. For example, Alzheimer's disease and Pick's disease both give progressive dementia without other prominent neurological signs. But the characteristic Alzheimer's neurofibrillary tangles are not seen in Pick's Disease, which has straight fibrils, as opposed to the paired helical filaments of Alzheimer's disease. Pick's Disease gives lobal atrophy, not seen in Alzheimer's disease. There are differences in origins, even with what little is known. Thus, among progressive dementias, CJD is definitely caused by an infectious agent; so far as can be determined, this is not so for Huntington's disease.
Even among hereditary disorders, the origins are different. Thus, FTDP-17 comes from chromosome 17, Huntington's disease from 4, and the neurodegenerative disorder that people with Down's syndrome develop later in life is presumably connected in some way to 21. The great majority of these have no treatment at all, and of those that do, none or virtually none have been treated with such agents as are disclosed here. The great diversity of diseases falling within the "neurodegenerative disorder" category means that it is contrary to medical understanding that any agent (let alone a genus of compounds) could be generally effective against such diseases. The intractability of these disorders is clear evidence that the skill level in this art is low relative to the difficulty of the task. Further, what little success there has been does not point in this direction.
No screening protocol(s) or methods of determining those expected to become afflicted are ever described. Thus, no evidence of in vitro or in vivo effectiveness is seen in the specification for one of the instantly claimed apomorphine prodrugs, particularly as they pertain to treating, preventing, or curing a neurodegenerative disease or disorder. In general, pharmacological activity is a very unpredictable area. In cases involving physiological activity "the scope of the enablement obviously varies inversely with the degree of unpredictability of the factors involved." In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970). Since this case involves unpredictable in-vivo physiological activities, the scope of the enablement given in the disclosure presented here was found to be low.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claims 14-16 and 20-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating sexual dysfunction, impotence, or restless leg syndrome, does not reasonably provide enablement for preventing or curing sexual dysfunction, impotence, or restless leg syndrome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The term “treatment” is defined on pages 20-21 of the specification (bridging paragraph) and said definition also embraces prevention (“prophylaxis”) and cure.
It is presumed “prevention” of the claimed disease would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted, nor are any of these conditions known in the art to be curable.
The factors to be considered in making an enablement rejection were summarized in the previous rejection. 1) As discussed above, preventing diseases requires identifying those patients who will acquire the disease before the prostate cancer occurs. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) The bridging paragraph on pages 20-21 defines treatment to include prevention and cure. 3) There is no working example of such a preventive or curative procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from sexual dysfunction, impotence, or restless leg syndrome before the fact, nor are these conditions purported to be curable by any known medicaments. Current treatments merely alleviate symptoms rather than fully reversing the causative condition. 6) The artisan using Applicants invention would be a Board-Certified physician with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention or cure of sexual dysfunction, impotence, or restless leg syndrome. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent sexual dysfunction, impotence, or restless leg syndrome. That is, the skill is so low that no compound effective generally in the prevention of sexual dysfunction, impotence, or restless leg syndrome. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases.
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) 1-8 and 10-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gupta et al. (US 2002002176 A1; 2002) in view of Dhareshwar et al. (Springer New York; 2020; IDS filed 12/05/2024).
Gupta et al. discloses derivatives of apomorphine of the following formula, which includes phosphate esters (p. 1-2; pars. [0010]-[0018]), wherein the derivatives are designed to reduce issues associated with low bioavailability and side effects (p. 1, par. [0006]).
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Gupta et al. discloses that the pharmaceutically acceptable salts must be suitable for administration to humans (p. 3, par. [0039]). Gupta et al. discloses a method of treating Parkinson’s disease and sexual dysfunction in a patient comprising administering a compound as above with apomorphine to enhance effectiveness of apomorphine (p. 2, pars. [0020]-[0022]) and discloses apomorphine derivatives including apomorphine O-glucuronide and apomorphine O-sulfate (p. 2, par. [0022]). Gupta et al. discloses the following structure of apomorphine (p. 5, par. [0057]).
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Gupta et al. additionally discloses that apomorphine acts as an emetic when administered subcutaneously at a dose of about 5 mg, and that the apomorphine should be administered in an amount sufficient to excite cells but with minimal side effects including nausea (p. 5, par. [0060]-[0061]).
While Gupta et al. does not explicitly teach an apomorphine derivative wherein one or both hydroxyl groups are substituted by phosphate (-O-P(=O)(-OH)(-OH), see instant claim 1), or wherein the salt is a sodium salt, these limitations are obvious over Dhareshwar et al.
Dhareshwar et al. teaches that formation of phosphate ester prodrugs, such as by incorporating a phosphate moiety into a hydroxyl group of the parent drug, improve aqueous solubility of poorly soluble phenol and alcohol group-bearing parent drugs (p. 46, par. 2). This strategy has been applied to drugs such as etoposide, a phenol-bearing antineoplastic agent, to reduce precipitation following dilution and when administered intravenously (p. 49-50, bridging paragraph). Dhareshwar et al. additionally discloses multiple examples of compounds converted to phosphate ester prodrugs wherein the counterion is sodium (p. 48, 51, 52).
It would be prima facie obvious for one of ordinary skill in the art to substitute one or both hydroxyl groups of apomorphine, as shown in Formula II of Gupta et al., with phosphate in order to form a phosphate ester prodrug. One would have been motivated to do so in order to improve the properties of apomorphine such as solubility and stability. One would have had a reasonable expectation of success as Gupta et al. sets forth phosphate as a substituent on the hydroxyl groups of the disclosed apomorphine derivatives, wherein a limited number of substituents and positions for substitution can be selected from. Moreover, one would have been apprised that a sodium salt would be a suitable salt form in view of Gupta et al. and Dhareshwar et al., wherein Gupta et al. discloses that the apomorphine derivatives include pharmaceutically acceptable salts, while Dhareshwar et al. exemplifies that sodium is a common counterion employed in formation of phosphate ester prodrugs.
It would additionally be prima facie obvious for one of ordinary skill in the art to select a mode of administration, such as subcutaneous administration. One would have been motivated to do so, with reasonable expectation of success, in order to determine the optimal administrative route to treat disorders such as Parkinson’s disease and sexual dysfunction, while also being apprised that the mode of administration and dose may be adjusted to avoid side effects and maintain efficacy.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/MADELINE E BRAUN/Examiner, Art Unit 1624 10/02/2026
