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 .
Status of the Application
Claims 1-20 are pending
Claims 1-20 are under consideration in the instant office action.
Priority
This application claims benefit of British Application No. GB 2016490.1 filed on 10/16/2020, British Application No. GB 2111343.6 filed on 08/05/2021, and PCT Application No. PCT/EP2021/078714 filed on 10/15/2021.
Claim Objections
Claim 8 is objected to because of the following informalities: “lisuride ergotamine nicergoline” should be written as “lisuride; ergotamine; nicergoline” and the term “dihydroergocomine” should be omitted. Appropriate correction is required.
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.
Claims 1-8, 10-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Durham (US 2019/0134011) in view of Takahashi et al. (Nicergoline inhibits T-type Ca2+ channels in rat isolated hippocampal CAl pyramidal neurons, Br. J. Pharmacology, 1990, 100, pp. 705-710).
Durham teaches “a pharmaceutical composition or a kit comprising, a first substance capable of raising intracellular cAMP levels, and a second substance capable of modulating intracellular calcium concentration. Likewise, the present invention relates to methods of treating patients suffering from autism spectrum disorder (ASD) phenotype 1 by administering an effective amount of a substance capable of raising intracellular cAMP levels and, optionally, an effective amount of a substance capable of modulating intracellular calcium concentration.” (see abstract). Durham teaches “Fragile X is the most common monogenetic cause of both intellectual disability and autism spectrum disorder. Patients with Fragile X syndrome (FXS), caused by loss of function of the fragile X mental retardation 1 (Fmr 1) gene, often exhibit many of the symptoms commonly associated with ASD, such as developmental delays, communication impairments and anxiety.” (paragraph 0007). Durham teaches substances capable of
modulating intracellular calcium concentration selected from a group that includes nicergoline (claim 12). Durham teaches a daily dosage of 1 to 150 mg divided among 1-3 doses (paragraph 0028).
Durham does not teach a motivation to select nicergoline as the substance capable of
modulating intracellular calcium concentration.
Takahashi et al. is drawn towards “the effect of nicergoline on the T-type Ca2 + channel in pyramidal neurones freshly isolated from the rat hippocampal CAI region” (Introduction). Takahashi et al. teaches “If the possibility is considered that T-type Ca2+ channels are linked strongly to Ca2"-mediated neurotoxity and that nicergoline blocks not only the L-type Ca2 + current but also the T-type Ca2 + current in hippocampal CAl pyramidal neurones (the present results), one of the protective effects of nicergoline on ischaemic brain damage may be due to its inhibitory actions on T- and L-type Ca2 + channels in brain cells.” (pg. 709, right column, second paragraph).
It would have been obvious to one of ordinary skill in the art to select nicergoline as the substance capable of modulating intracellular calcium concentration, as suggested by Takahashi et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Takahashi et al. teaches nicergoline as a dual calcium channel inhibitor that provides neuroprotective effects, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Even though the range for dosages as taught by Durham is not the same as the claimed dosages, Durham does teach an overlapping range of dosages (paragraph 0028), and it has been held that in the case where the claimed ranges “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). See MPEP § 2144.05(I). Furthermore, the determination of dosages is well within the purview of those skilled in the art through routine experimentation, and it has been held that “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). See MPEP § 2144.05(II). It would have been obvious to one of ordinary skill in the art to optimize the dosage in order to increase the efficacy of the composition.
The amounts of active agents to be used, the pharmaceutical forms, e.g., tablets, etc; mode of administration, flavors, surfactant are all deemed obvious since they are all within the knowledge of the skilled pharmacologist and represent conventional formulations and modes of administration.
Furthermore, no unobviousness is seen in the ratio claimed because once the usefulness of a compound is known to treat a condition, it is within the skill of the artisan to determine the optimum ratio.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Durham (US 2019/0134011) in view of Mizuno et al. (Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes, Brain Research, 2005, pp. 78-85) as applied to claims 1-8, 10-16, and 18-19 above, and further in view of Hanson (Serotonin dysregulation in Fragile X Syndrome: implications for treatment, Intractable & Rare Diseases Research, 2014, 3(4), pp. 110-117).
The teachings of Durham and Mizuno et al. are presented above.
Durham and Mizuno et al. does not teach further administrating an SSRI.
Hanson is drawn towards serotonin dysregulation in Fragile X Syndrome treatment (see abstract). Hanson teaches that “serotonin is dysregulated in FXS and treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline may be beneficial for individuals with FXS, particularly in early childhood.” (see abstract).
It would have been obvious to one of ordinary skill in the art to further administer an SSRI, as suggested by Hanson, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, it would have been prima facie obvious to combine nicergoline and sertraline in a composition cojointly to treat FXS and autism.
Allowable Subject Matter
Claims 9 and 17 appear free of the prior art.
The following is a statement of reasons for the indication of allowable subject matter: claims 9 and 17 recite “a substantially equiproportional preparation of dihydroergocornine, dihydroergocristine, and dihydroergocryptine” which are not obvious or anticipatory over the prior art.
Conclusion
Claims 1-8, 10-16, and 18-20 are rejected.
Claims 9 and 17 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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