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 .
DETAILED ACTION
**Note to Applicant**:
Examiner for this application has changed.
Please address all documents to Examiner Josmalen M. Ramos-Lewis, Ph.D.
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Review of Claim Status
Claims 1-30 are pending in the present application.
Priority Status
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Acknowledgment is made of applicant' s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
The certified copy Japanese and English translation had been filed in Application No. 18/084,367, filed on 12/19/2022.
The Instant Application based on the CON of 16/385,531 is acknowledged with an Effective Filing Date of 04/26/2019.
Information Disclosure Statement
All three (3) have been considered in the IDS(s) filed 12/19/2022, 05/29/2024, 12/05/2024 unless marked with a strikethrough.
Drawings
Examiner accepts the two (2) drawing submission filed 12/19/2022 for the Instant Application.
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.
Instant Claims 1-8, 10-25 rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-17 of U.S. Patent No. US 10,758,535 B1 in view of H. Tanaka in “Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain” (hereinafter “Tanaka”) and further in view of X. Huang in “Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms” (hereinafter “Huang”).
Although the claims at issue are not identical, they are not patentably distinct from each other because as Patent ’535 shows, the Instant Claims recite treating, improving, delaying the progression, or preventing symptoms in Parkinson’s Disease through the administration of tandospirone parenterally – which bypasses the gut – and is able to provide alleviation to displayed symptoms.
Instant Application No. 18/084,367
The claims of 18/084,367 recite:
(Patent Claim ‘535 overlap)
U.S. Patent No. US 10,758,535 B1
The claims of US 10,758,535 B1 recite:
1. A method for treating, improving, delaying the progression, or preventing dyskinesia in a subject, comprising parenterally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt (‘535 - Claim 1) or prodrug thereof is administered so that a human blood (plasma) tandospirone concentration is 0.1 to 15 ng/mL for 12 hours or longer per day (‘535 - Claims 13-14); and/or 0.1 to 15 ng/mL for 8 to 16 hours after administration of the tandospirone (‘535 - Claims 13-14) or a pharmaceutically acceptable salt or prodrug thereof.
2. The method according to claim 1, wherein the patient is suffered from Parkinson's disease (‘535 - Claim 1).
3. The method according to claim 1, wherein the subject is subject to a drug therapy of Parkinson's disease (‘535 - Claim 1).
4. The method according to claim 1, wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of Parkinson's disease drug therapy such as levodopa therapy (‘535 - Claims 1, 17), a therapy with levodopa metabolism enzyme inhibitor and Dopamine receptor agonist; and Parkinson's disease adjunct.
5. The method according to claim 1, wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of dopamine replacement therapies such as levodopa therapy (‘535 – Claims 1, 17), a therapy with levodopa metabolism enzyme inhibitor and a dopamine receptor agonist.
6 The method according to claim 1, wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of levodopa therapies such as therapy with levodopa containing formulation (‘535 - Claims 1, 17), and a therapy with levodopa metabolism enzyme inhibitor and a dopamine receptor agonist.
7. The method according to claim 1, wherein dopamine amount in striatal synaptic cleft of the subject is sustainably maintained and/or suppressing rapid changes (‘535 – Claim 2).
8. The method according to claim 1, wherein the administration is performed without inducing rebound symptoms in the subject (‘535 - Claim 1) .
10. The method of claim 1, wherein the parenteral administration comprises transdermal administration (‘535 - Claims 1, 7).
11.The method of claim 1, wherein the treatment, improvement, delay of progression, or prevention improves dyskinesia without a rebound symptom (‘535 - Claims 1, 4).
12. The method of claim 1, wherein the dyskinesia comprises at least one of the group consisting of peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof (‘535 - Claim 3).
13.The method of claim 1, wherein the treatment, improvement, delay of progression, or prevention of dyskinesia comprises improvement, delay of progression, or prevention of a dyskinesia symptom (‘535 - Claim 4), reduction of a period of PD-LID manifestation (‘535 - Claim 1), or a combination thereof.
14. The method of claim 13, wherein the improvement of a dyskinesia symptom is a clinically significant improvement or greater (‘535 – Claims 4 - 6).
15. The method of claim 13, wherein the improvement of a dyskinesia symptom is to a sufficient level to attain a clinical effect (‘535 - Claims 4 - 6).
16. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermally administered formulation (‘535 - Claims 1-2, 7).
17. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as an adhesive formulation (‘535 - Claims 1, 7).
18. The method of claim 10, wherein the transdermally administered formulation is a tape/patch (‘535 - Claims 1, 7-9).
19. The method of claim 1, wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day (‘535 – Claims 1, 10-11) as a free form of tandospirone.
20. The method of claim 1, wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt (‘535 - Claims 1, 7-9) or prodrug thereof is 0.1 to 20 mg per day as a free form of tandospirone (‘535 – Claims 10-11).
21. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermally administered formulation, (‘535 – Claims 1, 7-9) and a total applied area per dose is 1 to 100 cm2 (‘535 – Claim 12).
22. The method of claim 1, wherein the human blood (plasma) tandospirone concentration is 1 to 12 ng/mL (‘535 – Claims 13-14).
23 The method of claim 1, wherein the human blood (plasma) tandospirone concentration is 2 to 10 ng/mL (‘535 – Claims 13-14).
24. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of levodopa (‘535 – Claim 15).
25. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is used with levodopa as the fixed-dose combination or concomitantly as separate formulations (‘535 – Claim 12).
1. A method for treating, or improving levodopa induced dyskinesia in Parkinson's disease (PD-LID) in a subject, comprising transdermally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone treats or improves PD-LID without a rebound symptom.
2. The method of claim 1, wherein the transdermal administration has sustainability or is sustainably administered.
3. The method of claim 1, wherein the PD-LID comprises peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof.
4. The method of claim 1, wherein the tandospirone treatment or improvement comprises treatment or improvement symptom, reduction of a period of PD-LID manifestation, or a combination thereof.
5. The method of claim 4, wherein the improvement of a PD-LID symptom is a clinically significant improvement or greater.
6. The method of claim 4, wherein the improvement of a PD-LID symptom is to a sufficient level to attain a clinical effect.
7. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation.
8. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as an adhesive formulation.
9. The method of claim 7, wherein the transdermally administered formulation is a tape/patch.
10. The method of claim 1, wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as a free form of tandospirone.
11. The method of claim 1, wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone.
12. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation, in a total applied area per dose of 1 to 100 cm2.
13. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a human blood (plasma) tandospirone concentration is 0.05 to 20 ng/mL for 12 hours or longer per day.
14. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a human blood (plasma) tandospirone concentration is 0.05 to 20 ng/mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
15. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is an adjunct of levodopa.
16. The method of claim 1, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used with levodopa as a fixed-dose combination or concomitantly as separate formulations.
17. The method of claim 16, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) an effective amount of levodopa or (2) levodopa and a metabolizing enzyme inhibitor of levodopa are administered simultaneously or at different times.
With respect to Instant Claims 1-8 and 10-25, US Patent 10,758,535 B1 recite methods of treating using the compound tandospirone, methods of treating a subject to a drug therapy of Parkinson’s disease with/without an adjunct, methods of treating a subject to a drug therapy of Parkinson’s disease using a range of human blood (plasma) tandospirone concentration of 0.05 to 20 ng/mL for 8 to 16 hours after administration of the tandospirone; all of which read on the Instant Claims (listed within the Table above, patent ‘535 claims recited on the right in blue, overlap with the Instant Application claims recited on the left in black; reference to Patent ‘535 is in parenthesis).
The use of the compound tandospirone has been successfully used in the art and in areas of dyskinesia (including Parkinson-related) since both are well-known in uses and methods just like the Instant claims. It therefore would be prima facie obvious to arrive at the instantly claimed compounds because structurally similar compounds are expected to have similar properties. In the matter of the Instant Application and the referenced patent, in this case the genus of the claims of the ‘535 patent disclose overlapping tandospirone formulations, parenteral administration, dose combination and formulations, and suggests the combinations taught.
The claims of the ‘535 patent fail to teach the tandospirone or a pharmaceutically acceptable salt is administered so that human blood (plasma) tandospirone concentration is 0.1 to 15 ng/mL for 12 hours or longer per day and/or 0.1 to 15 ng/mL for 8 to 16 hours after administration of the tandospirone.
However, using the prior art of Tanaka titled “Effects of Tandospirone on Second Messenger Systems and Neurotransmitter Release in the Rat Brain,” with respect to Instant Claims 1-8 and 10-25 one may well use KSR – Prong A since both OH-DPAT and tandospirone are known in the art for : 1) as both are 5-HT1A agonist receptors; 2) Tandospirone is an established medication (since 1996) used to treat CNS disorders, according to the National Institutes of Health (NIH), so its use clinically would be met with success. As seen in Tanaka, the action of tandospirone on the neurotransmitter release indicates its pharmacological and clinical profile is seen on Table 1 & 2 (pg. 1768-1969; Table 1 also shows comparison to the another 5-HT agonist, OH-DPAT; Table 2 shows the effect of tandospirone, its metabolite 1PP on brain hippocampus).
It therefore would be prima facie obvious to arrive at the instantly claimed compounds and methods of tandospirone because structurally similar compounds are expected to have similar properties. In the matter of the Instant Application and the prior art Tanaka, the compound of the Instant claims, tandospirone discloses the action of tandospirone shown to
act as partial agonists for serotonin lA (5-HT1A) receptors on neurotransmitter release. The effects of tandospirone, on the intercellular second messenger systems (adenylate cyclase and phosphatidylinositol metabolic systems) were examined using rat hippocampi, in comparison with 5-HTIA receptor agonists, 5-HT and 8-OH-DPAT, and other 5-HT1A receptor-related anxiolytics (pg. 1771, col. 1, full para. 1). Tandospirone influences monoamine metabolism in vivo. Tandospirone, at the dose exhibiting anti-conflict action in vivo, suppressed 5-HT metabolism, and increased NE (norepinephrine)and DA (dopamine) metabolism in various brain regions such as cerebral cortex, hippocampus, striatum, hypothalamus, mesencephalon. The mechanism of the tandospirone formulations reads on the instant claims and as are the overlapping tandospirone formulations, parenteral administration, dose combination and formulations, and suggests the combinations taught.
Additionally, with respect to Instant Claims 1-8 and 10-25, the prior art of Huang titled “Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms” the compound of the Instant claims (tandospirone and its intended use for Parkinson’s and dyskinesia) is revealed to have a “beneficial effect of an improvement of motor dysfunction of Parkinson's disease and cognitive deficits of schizophrenia either in monotherapy or in combination with other drugs.” The review discusses the superiority of tandospirone in the treatment of the disorders and associated mechanisms in central nervous system as well as Parkinson’s Disease (pg. 102709, Tandospirone in the treatment of Parkinson’s disease). Huang teaches “Intrastriatal injection of 5-HT at doses compatible to those of dopamine (5-HT, 25–100 μg; dopamine, 50–100 μg) caused a contralateral circling behavior in rats, implying that the striatal 5-HT1A receptors played a role in antiparkinsonian effects (pg. 102709, col. 2, ending para.).
It therefore would be prima facie obvious to arrive at the instantly claimed compounds and methods of tandospirone because structurally similar compounds are expected to have similar properties. In the matter of the Instant Application and the prior art Huang, the compound of the Instant claims, tandospirone, discloses the action of tandospirone shown to
act as partial agonists for serotonin IA (5-HT1A) receptors on neurotransmitter release. The prior art of Huang discloses “In a recent study, tandospirone attenuated L-dopa induced peak abnormal involuntary movements (AIM) scores by about 40% at the highest dose (2.5 mg/kg) but failed to significantly reduce the total AIMs scores in one testing session. In the same study, tandospirone (0.16 mg/kg, 0.63 mg/kg, and 2.50 mg/kg) did not improve the effect of L-dopa in cylinder and rotational behavior test, and decreased the effect of L-dopa in rotarod performance at the highest dose (pg. 102710, col. 1, full para. 1).” These ranges read within the ranges claimed in the Instant Application.
Also, Huang teaches Tandospirone Citrate (brand name of Sediel) was first synthesized by Dainippon Sumitomo Pharmaceuticals in 1980 and marketed in 1996 in Japan. It was available in China in 2004. In both countries, tandospirone was permitted for the treatment of anxiety disorder especially generalized anxiety disorder and anxiety associated with primary hypertension or peptic ulcer. Besides, tandospirone showed the efficacy in treating other CNS disorders such as depression, Parkinson’s disease and schizophrenia in recent clinical and preclinical studies.
Thus KSR – Prong A can be used because: 1) Huang discloses the same 5-HT1A agonist; 2) Tandospirone is an established medication (since 1996) used to treat CNS disorders, according to the National Institutes of Health (NIH), so its use is clinically met with success.
Claim Rejections - 35 USC § 112
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 1, 16-17, 19-21, 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), because the specification, while being enabling for levodopa-induced dyskinesia, it does not reasonably provide enablement for prodrugs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability or unpredictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claims recite the compound tandospirone and its pharmaceutically acceptable salt, or prodrug thereof for the use of this compound and the treatment of dyskinesia.
Breadth of the Claims: The instant claims include no list of potential prodrugs embraced by the claims.
State of the art & predictability or unpredictability of the art: As early as 1995, Tandospirone, as well as buspirone, gepirone and ipsapirone, are anxiolytic piperazine derivatives that have pharmacological and clinical efficacy. In the prior art of H. Tanaka, et. al in “Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain.” The study went over the effects of tandospirone, a 5-HTIA receptor-related anxiolytic, on the intercellular second messenger systems (adenylate cyclase and phosphatidylinositol metabolic systems) examined using rat hippocampi, in comparison with 5-HTIA receptor agonists, 5-HT and 8-OH-DPAT, and other 5-HT1A receptor-related anxiolytics.
Tanaka represents the earliest example of the art. As seen by the Tanaka, the action of tandospirone on the neurotransmitter release indicates its pharmacological and clinical profile is seen on Table 1 & 2 (pg. 1768-1969; Table 1 also shows comparison to the another 5-HT agonist, OH-DPAT; Table 2 shows the effect of tandospirone, its metabolite 1PP on brain hippocampus).
Currently, as of October 2017, the prior art of X. Huang, et al discloses the “Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms.” In this, the beneficial effect of tandospirone revealed an improvement of motor dysfunction of Parkinson's disease and cognitive deficits of schizophrenia either in monotherapy or in combination with other drugs.” The review discusses the superiority of tandospirone in the treatment of the disorders and associated mechanisms in central nervous system from the literature. As such, the predictability is high with the current literature as of 2017 with respect to the base compound, but the literature is silent on prodrugs of tandospirone.
There are no examples of a prodrug of the compound of tandospirone in the Instant Specification. There are no examples showing that modifications of the base drug as a pro-drug – esterification, etc – would maintain its function.
Guidance of the specification: The only direction concerning prodrugs of the compound of claims 1, 16-17, 19-21, 24-25 in the instant specification is in the form of a definition of “prodrug”. Reference to the “prodrugs” is not defined or used. The Instant specification does not define “prodrug”. The specification does not provide guidance on what will make the prodrugs of this invention or how the compound would be modified.
Tandospirone is defined as a partial agonist of the 5-HT-1A receptor, developed as a non-benzodiazepine anxiolytic that can modulate activity in the brain's fear circuitry and affect gastrointestinal physiology. There is no mention in this though, as to how a prodrug would be used in this case.
Existence of working examples/specification: There are no examples of a prodrug of the compound of tandospirone in the Specification. There is no guidance as to what position of the molecule would be modified to provide the prodrug, and there are no examples showing that such compounds would maintain function.
Predicting whether a recited compound is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty. The instant disclosure provides no evidence to suggest that this unique activity can be achieved utilizing a prodrug of tandospirone, for example, that is bioactivated either inside or outside of the cell and thus possess contrasting mechanisms of action,
and thus does not meet the “how to use” prong of 35 USC 112, first paragraph.
Amount of experimentation necessary: Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed compound, for example, is in fact a prodrug, that produces the active compound metabolically in man at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be clinically effective. First, preparing, then determining whether a particular compound meets these three criteria in a clinical trial setting requires an undue quantity of experimentation.
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. Thus, undue experimentation will be required to determine if any particular derivative is, in fact, a prodrug.
After consideration of nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability or unpredictability of the art and the amount of experimentation necessary, Applicant was not in possession of the entirety the genus of a “prodrug”.
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.
Joint Inventors
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 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over Wolf in US 9,066,903 B2 (pub’d: 06/30/2015; hereinafter “’903”), and in view of Jin F. in “Determination of tandospirone in human plasma by a liquid chromatography-tandem mass spectrometry method” (pub’d: 05/01/2011; hereinafter “Jin”), as evidenced by Merriam Webster.
With respect to the Claim 1, Patent’903 discloses a method for treating (col. 3, lns. 13-15; methods for treating Parkinson's disease), improving, delaying the progression, or preventing dyskinesia (col. 3, lns. 35-40; In some preferred embodiments, the at least one side effect of the dopamine receptor agonist comprises dyskinesia - e.g., one or more of chewing, gnawing, twisting, tongue or mouth movements, head bobbing, and movements of the feet, hands, or shoulder) in a subject, comprising parenterally administering to the subject an effective amount of tandospirone (col. 9, lns. 15-32; The preferred serotonin - 5-HT receptor agonists for use.. are full agonists at the 5-HTlA receptor subtype, or partial agonists with moderate to high efficacy at the 5-HTlA receptor subtype. Particular examples of such compounds include phenylpiperazines such as tandospirone…Particular examples also include substituted chromane derivatives such as sarizotan, 8-OHDPAT, alnespirone, BAY X 3702…) or a pharmaceutically acceptable salt or prodrug thereof.
Patent’903 fails to recite (in Claim 1) parenteral administration is used for the method for treating, improving, delaying the progression, or preventing dyskinesia. It is implied though the examples that Patent’903 discloses one of the common routes used in parenteral treatment, subcutaneous injection, as in the Examples.
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According to the Merriam-Webster Dictionary:
As such, Broadest Reasonable Interpretation indicates subcutaneous injections given to subjects, as seen in Example 1 & 2 (col. 11 - col. 13), demonstrate the scope of the claim but also read on parenteral administration of treatment. As seen in the Instant Specification, para. [0120], “…continuous subcutaneous infusion of tandospirone dose-dependently improved dyskinesia-like symptoms. The administration did not lead to a rebound symptom at any of the dosages.” This, as well as the secondary example of parenteral administration in the Instant Specification, para. [0127]; “the effect of improving PD-LID symptoms was sustained even after continuous subcutaneous infusion of tandospirone for 13 days” reads on the claims.
Patent’903 also fails to disclose (in Claim 1) wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered so that a human blood (plasma) tandospirone concentration is 0.1 to 15 ng/mL for 12 hours or longer per day; and/or 0.1 to 15 ng/mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof.
The reference of Jin discloses “…(tandospirone) is an anxiolytic agent of the azapirone class, and is a serotonin 1A receptor agonist….Tandospirone also seems to be effective against depression and other anxiety disorders because serotonin 1A receptor agonists produce downregulation of postsynaptic serotonin 2 receptors. The oral dosage of tandospirone is 10–20 mg/day in China, and the concentration of tandospirone in plasma is low (pg. 2881, col. 2, para. 1)”.
Jin also discloses since the concentration in plasma is low, LC-MS/MS optimization as seen in Figure 3, pg. 2886, discloses the concentration range of claim 1. Jin discloses the range of 0.01 to 2 ng/mL for 8 to 12 hours after administration of the tandospirone (which reads on the claim language). In doing so, the “LC−MS/MS method validated the determination of tandospirone in human plasma. The method is rapid, sensitive, and highly selective, with a LLOQ of 10 pg/ml (which is 0.1 ng/ml) using 0.25 ml human plasma (pg. 2887, col. 2, para. 1; which indicates the LLOQ taught is at least 0.1 ng/ml, which also reads on the claim as reading on the lower limit of the range).
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Therefore it would be obvious to use the combination of Patent’903 which discloses methods and compositions (‘903 – col. 7, lns. 19-21) for “alleviation of akinesia, rigidity and/or tremor associated with Parkinson's disease” and Jin (pg. 2887) which discloses the method of detection for tandospirone, as well as an example of use within a subject. Jin discloses a “validated analytical method and for its application to evaluate the bioequivalence of two tandospirone citrate tablet formulations in 18 healthy male volunteers. Both tandospirone formulations were well tolerated at the dose administered. The means of the plasma concentrations of tandospirone are shown in Fig. 3. The test formulation was considered bioequivalent to the reference formulation according to both the rate and the extent of absorption.”
Both prior arts disclose tandospirone, as an anxiolytic agent of the azapirone class, and as a serotonin 1A receptor agonists. Also in the art, OH-DPAT is a serotonin type IA/5-HT1A receptor agonist. It primarily acts as a potent, selective centrally acting 5-HT agonist. OH-DPAT is a research tool that acts as a potent 5-HT1A full agonist with effects on other 5-HT receptors and processes. Tandospirone is a potent and selective 5-HT1A receptor partial agonist. It functions as a full agonist at 5-HT1A autoreceptors (which respond to the neurotransmitter released by that neuron, and contribute to the regulation of the synthesis and release of the neurotransmitter itself) and a partial agonist at postsynaptic 5-HT1A receptor.
By applying prong A of KSR, one skilled in the art could use either compounds successfully in areas of dyskinesia since both are well-known in uses and methods just like the Instant claims. One in the art could also substitute the OH-DPAT with tandospirone because: 1. They are both 5-HT1A agonist receptors; 2. Tandospirone is an established medication (since 1996) used to treat CNS disorders, according to the National Institutes of Health (NIH), so its use clinically would be met with success.
With respect to Claims 2-8 & 11, Patent’903 continues to disclose:
Claim 2: wherein the patient is suffered from Parkinson's disease (col. 3, lns. 13-15; methods for treating Parkinson's disease).
Claim 3: wherein the subject is subject to a drug therapy of Parkinson's disease (col. 1, lns. 44-49; Most current treatment strategies for Parkinson's disease, PD, focus on symptom control through one or more of medication, surgery, and physical therapy. The dopamine precursor, levodopa L-DOPA is still considered to be the gold standard in terms of treatment for PD).
Claims 4-6: wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of Parkinson's disease drug therapy such as levodopa therapy, a therapy with levodopa metabolism enzyme inhibitor and Dopamine receptor agonist and Parkinson's disease adjunct ((col. 8, lns. 40-44) D2 agonists have been utilized as monotherapy for mild or early stage PD and as adjuncts to L-DOPA in more advanced PD).
Claims 7: wherein dopamine amount in striatal synaptic cleft of the subject is sustainably maintained (col. 7, lns. 23- 67 to col. 8, lns. 1-12)
Claims 8 & 11: wherein the administration is performed without inducing rebound symptoms in the subject; wherein the treatment, improvement, delay of progression, or prevention improves dyskinesia without a rebound symptom (col 3, lns. 46-66; “…provides methods for treating a subject, comprising: providing; i) a serotonin type IA (5-HTIA) receptor agonist, ii) a dopamine receptor agonist, iii) a subject receiving the dopamine receptor agonist for treatment of Parkinson's disease, wherein the subject is suffering from dopamine receptor agonist-induced dyskinesia; co-administering the serotonin type IA receptor (5-HTIA) agonist in combination with the dopamine receptor agonist to the subject during a preconditioning period under conditions suitable for reducing the dopamine receptor agonist-induced dyskinesia; co-administering the serotonin type IA receptor (5-HTIA) agonist in combination with the dopamine receptor agonist to the subject during a dosage optimization period, wherein dosage of the dopamine receptor agonist is gradually reduced until at least one symptom of the Parkinson's disease is re-emerges; and co-administering the serotonin type IA receptor (5-HTIA) agonist in combination with the dopamine receptor agonist to the subject under conditions suitable for reducing the at least one symptom of the Parkinson's disease, while reducing the dopamine receptor agonist-induced dyskinesia).
With respect to Claims 12-15, Patent’903 discloses different types of dyskinesia:
Claim 12: wherein the dyskinesia comprises at least one of the group consisting of peak-dose dyskinesia (col. 4, lns. 49-51; FIG. 5 demonstrates repeated administration of 5-HTIA agonist reduced dyskinetic behavior elicited by a moderately high dose of the DI agonist which reads on peak-dose dyskinesia).
Claim 13: wherein the treatment, improvement, delay of progression, or prevention of dyskinesia comprises improvement, delay of progression, or prevention of a dyskinesia symptom, reduction of a period of PD-LID manifestation, or a combination thereof (col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
Claim 14: wherein the improvement of a dyskinesia symptom is a clinically significant improvement or greater (col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
Claim 15: wherein the improvement of a dyskinesia symptom is to a sufficient level to attain a clinical effect (col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
With respect to Claims 10, 16-18, Patent’903 discloses transdermal administration:
Claim 10: wherein the parenteral administration comprises transdermal administration (col. 2, lns. 38-41; In some preferred embodiments, 8-OH-DPAT - a serotonin type IA/5-HT1A receptor agonist - is administered via a transdermal patch. In some embodiments, the serotonin type IA - 5-HT1A - receptor agonist is selected from the group consisting of tandospirone).
Claim 16: wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermally administered formulation (col. 2, lns. 38-41).
Claim 17: wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as an adhesive formulation (col. 2, lns. 38-41).
Claim 18: wherein the transdermally administered formulation is a tape/patch (col. 2, lns. 38-41).
Patent ’903 fails to recite (in Claims 10, 16-18) the parenteral administration, specifically transdermal administration in the specific adhesive, tape or patch. However, the reference, does disclose the parenteral administration as a transdermal patch. As such, under BRI, this reads on the claims for transdermally administered adhesive, tape or patch since transdermal patches are non-invasive and often convenient way for an active ingredient to slowly diffuses through the layers of the skin, eventually reaching the bloodstream.
With respect to Claims 24-28, Patent’903 continues to disclose administration and therapy:
Claim 24: wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of levodopa (col. 8, lns. 40-45; D2 agonists have been utilized as monotherapy for mild or early stage PD and as adjuncts to L-DOPA in more advanced PD).
Claim 25: wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is used with levodopa as the fixed-dose combination or concomitantly as separate formulations (col. 2, lns. 23-26; co-administering the 5-HTIA agonist in combination with a low dose of the dopamine receptor agonist to the subject, under conditions suitable for reducing at least one symptom of the motor disorder).
Claim 26: wherein the method further improves motor fluctuations in the subject (col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
Claim 27: wherein the motor fluctuations comprise at least one of the group consisting of a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, a delayed on phenomenon, and a combination thereof (col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
Claim 28: wherein treatment, improvement, or prevention of the motor fluctuations comprises prolongation of an antiparkinsonian action effective time (ON-time), a reduction of a non-response time (OFF-time), or a combination thereof (col. 8, lns. 21-34 & col. 10, lns. 33-67 to col. 11, lns. 1-28; Example 1).
With respect to Claims 19-20, 22-23, and 29-30, Patent ’903 fails to disclose drug dosages of the tandospirone or a pharmaceutically acceptable salt or prodrug.
For Claims 19-20, 22-23, 29-30, Jin discloses the following drug dosage ranges:
Claim 19: wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg (pg. 2881, col. 2, para. 1; The oral dosage of tandospirone is 10–20 mg/day in China and the concentration of tandospirone in plasma is low). Jin discloses the concentration in plasma is low in the range of 0.01 to 2 ng/mL for 8 to 12 hours after administration of the tandospirone (pg. 2881, col. 2. para. 1; pg. 2886, Figure 3, giving the LLOQ for tandospirone in the blood - which reads on the claim language).
Claim 20: wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 20 mg (pg. 2881, col. 2, para. 1; The oral dosage of tandospirone is 10–20 mg/day in China and the concentration of tandospirone in plasma is low). Jin discloses the concentration in plasma is low in the range of 0.01 to 2 ng/mL for 8 to 12 hours after administration of the tandospirone (pg. 2881, col. 2. para. 1; pg. 2886, Figure 3, giving the LLOQ for tandospirone in the blood - which reads on the claim language)
Claim 22: wherein the human blood (plasma) tandospirone concentration is 1 to 12 ng/mL Jin discloses the concentration in plasma is low in the range of 0.01 to 2 ng/mL for 8 to 12 hours after administration of the tandospirone (pg. 2881, col. 2. para. 1; pg. 2886, Figure 3, giving the LLOQ for tandospirone in the blood - which reads on the claim language)
Claim 23: wherein the human blood (plasma) tandospirone concentration is 2 to 10 ng/ml Jin discloses the concentration in plasma is low in the range of 0.01 to 2 ng/mL for 8 to 12 hours after administration of the tandospirone (pg. 2881, col. 2. para. 1; pg. 2886, Figure 3, giving the LLOQ for tandospirone in the blood - which reads on the upper limit claim language)
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Claim 29: wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a maximum blood concentration of human blood (plasma) tandospirone in a steady state is 1 to 15 ng/mL (according to BRI, in Figure 3 on pg. 2886, the ratio where 30-95% of the administration of tandospirone at a steady range would be in the range of 1.0-1.4 ng/mL) and a ratio of a minimum concentration, with respect to the maximum concentration of human blood (plasma) tandospirone concentration as 100%, is 30 to 95% after administration of the tandospirone (according to BRI, in Figure 3 on pg. 2886, the ratio where 30-95% of the administration of tandospirone would be in the range of 1.0-1.4 ng/mL) or a pharmaceutically acceptable salt thereof.
Claim 30: Jin recites wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a maximum blood concentration of human blood (plasma) tandospirone in a steady state is 2 to 12 ng/mL (according to BRI, in Figure 3 on pg. 2886, the ratio where 30-95% of the administration of tandospirone for the lower range of the prior art is 2.0 ng/mL, and as such the peak amount needed of tandospirone is low in plasma levels as indicated by the prior art, as well as the test into male volunteers which indicated a maximum blood concentration at ~1.4 ng/mL), and a ratio of a minimum concentration, with respect to the maximum concentration of human blood (plasma) tandospirone concentration as 100%, is 30 to 95% after administration of the tandospirone (according to BRI, in Figure 3, the ratio where 30-95% of the administration of tandospirone would be in the range of 1.0-1.4 ng/mL) or a pharmaceutically acceptable salt thereof.
Therefore it would be obvious to use the combination of Patent’903 (abstract) which discloses “methods and compositions for alleviation of akinesia, rigidity and/or tremor associated with Parkinson's disease” with the method of detection for the tandospirone, as well as an examples of use within a subject. Jin discloses (pg. 2887) a “validated analytical method and for its application to evaluate the bioequivalence of two tandospirone citrate tablet formulations in 18 healthy male volunteers. Both tandospirone formulations were well tolerated at the dose administered. The means of the plasma concentrations of tandospirone are shown in Fig. 3 of Jin. The test formulation was considered bioequivalent to the reference formulation according to both the rate and the extent of absorption.”
Both prior arts disclose tandospirone, as well as tandospirone is an anxiolytic agent of the azapirone class, and is a serotonin 1A receptor agonists. Also in the art, OH-DPAT is a serotonin type IA/5-HT1A receptor agonist. It primarily acts as a potent, selective centrally acting 5-HT agonist. OH-DPAT is a research tool that acts as a potent 5-HT1A full agonist with effects on other 5-HT receptors and processes. Tandospirone is a potent and selective 5-HT1A receptor partial agonist. It functions as a full agonist at 5-HT1A autoreceptors (which respond to the neurotransmitter released by that neuron, and contribute to the regulation of the synthesis and release of the neurotransmitter itself) and a partial agonist at postsynaptic 5-HT1A receptor. By applying prong A of KSR, one skilled in the art could use these compounds since they are well-known in the art and methods of use to arrive at the instant claims. One in the art could also substitute the OH-DPAT with tandospirone because: 1. They are both 5-HT1A agonist receptors; 2. Tandospirone is an established medication (since 1996) used to treat CNS disorders, according to the National Institutes of Health (NIH).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Patent’903, in view of Jin and further in view of E.C. Hirsch, in “Inflammatory Changes and Apoptosis in Parkinson’s Disease” (pub’d 2002; hereinafter “Hirsch”), as evidenced by Merriam Webster.
The combination of Patent’903 and Jin disclosed above and at least those teachings are incorporated by reference herein.
With respect to Claim 9, Patent’903 fails to recite fluxes in the striatum of the subject using "1C-raclopride Positron Emission Tomography (PET).
Claim 9: the prior art of Hirsch discloses wherein a levodopa-evoked synaptic dopamine fluxes in the striatum of the subject using 1C-raclopride Positron Emission Tomography (PET) test is sustainably maintained, and/or suppressing rapid changes and/or intermittent domain receptor stimulation is suppressed (pg. 259, para. 1).
Therefore it would be obvious to use the combination of Patent’903 and Jin which discloses methods and compositions for alleviation of akinesia, rigidity and/or tremor associated with Parkinson's disease, blood plasma dosage for tandospirone with t