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 Claims
Claims 30-55 are pending.
Priority
Instant application 18/113,887, filed 02/24/2023 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 02/24/2023, 05/29/2024, 12/05/2024, and 09/24/2025 have been considered unless marked with a strikethrough.
Claim Interpretation
Claim 30 recites a method of treating, improving, or preventing “motor fluctuations”. The term “motor fluctuations” is being interpreted according to the definition provided in the as-filed specification at page 141, para. [0038]:
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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 30-54 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 a method of prolongation of an antiparkinsonian action effective time (ON-time) or a reduction of an antiparkinsonian action non-response time (OFF-time) in a patient with Parkinson’s disease, wherein the patient is being treated with levodopa;
does not reasonably provide enablement for a method of treating, improving, or preventing motor fluctuations in a subject in need thereof.
Stated differently, while the method of claim 55 is considered to be enabled; the “prevention” of motor fluctuations and the broader patient population (beyond patients receiving levodopa therapy for PD) in the method of claim 30 and dependent claims are not considered to be enabled. 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 examiner has followed the guidance in MPEP 2164 and In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), and has considered the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to uses of the 5-HT1A receptor agonist tandospirone or pharmaceutically acceptable salts thereof, administered transdermally. One of the uses is a method of treating, improving, or preventing motor fluctuations comprising transdermally administering tandospirone or a pharmaceutically acceptable salt thereof to a subject in need thereof. The specification and claims contemplate the administration of tandospirone to a patient undergoing drug therapy in order to treat, improve, or prevent motor fluctuations in said patient.
Breadth of the claims:
The claims are broadly directed to the use of compounds of formula (I) in methods for the treatment or prophylaxis of motor fluctuations. The term “motor fluctuations” is defined at page 141, para. [0038] to mean reduction in the time during which a drug is effective and loss of an effect until the next dose. The claims therefore embrace treatment, improvement, or prevention of a reduction in the time during which a drug is effective and loss of an effect until the next dose in a broad patient population.
Level of ordinary skill in the art:
The artisans in the field of applicant’s invention include a collaborative team comprising medicinal chemists, neuroscientists, pharmacologists, and/or healthcare practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience. The level of skill in the art is high; however, the pharmaceutical arts are generally characterized as unpredictable despite the high level of skill.
State of the prior art and predictability in the art:
The use of 5-HT1A agonists in PD patients is still under investigation, with mixed results reported in the prior art. See, for example, Stayte et al. (Frontiers in Neuroscience, vol. 8, May 2014, p. 113), which is a review article drawn to advances in non-dopaminergic treatments for Parkinson’s disease (title). Stayte discusses serotonin (5-HT) receptor agonists at page 12. In particular, Stayte teaches that “recent evidence strongly suggests that 5-HT neurons may play an important role in L-dopa-induced DA [dopamine] release and thus LIDs [levodopa-induced dyskinesias]” (page 12, left side, second para.).
Stayte further teaches: “This finding that 5-HT may regulate L-Dopa-induced DA release has led to the investigation of molecules acting on 5-HT receptors as anti-dyskinetic drugs… the autoreceptors 5-HT1A and 5-HT1B are among the most studied in PD…Stimulating 5-HT1A and 5-HT1B via 8-OH-DPAT and CP-94253, respectively, has been shown to…attenuate the expression of LIDs in rats” (page 12, left side, third para.).
Stayte further teaches that the findings in animal models “have resulted in an open label, multicenter trial of the 5-HT1A agonist sarizotan’s safety, tolerability and efficacy in patients with advanced PD complicated by troublesome LIDs. Sarizotan treatment significantly reduced dyskinesias as measured by home diary, AIMS, and UPDRS scores. Furthermore, dyskinesia benefits were obtained without change in total “off” time or in change from baseline mean UPDRS scores. However, while initially exciting, several patients experienced worsening parkinsonism with sarizotan or with increasing doses, due to the fact that sarizotan not only antagonizes 5-HT1A receptors but also blocks the D4 DA receptor. These disappointing results do not rule out the value of targeting 5-HT receptors, but instead suggest that sarizotan may not be the ideal therapeutic for treating LIDs.” (page 12, right side, first para.)
Stayte further teaches that a “number of small clinical trials have been conducted investigating other 5-HT1A receptor agonists. In a double-blind, placebo-controlled study, buspirone significantly lessened the severity of LIDs in 5 out of the 7 patients but proved ineffective in the remaining 2 who had the mildest dyskinesias. Another 5-HT1A agonist with 5-HT2 antagonism, mirtazapine, was shown in an open label study to be moderately effective in reducing LIDs both alone and in combination with amantadine. In addition, a number of partial 5-HT agonists, including clozapine (Durif et al., 1997, 2004), tandospirone and aripiprazole have also shown some limited success at attenuating dyskinesias.” (page 12, right side, second para.)
Please note that in view of the teachings above, Stayte is considered to highlight the unpredictable nature of 5-HT1A receptor agonists and their utility in PD patients. The anti-dyskinetic effects of 5-HT1A agonists appears to vary across different patients and across different 5-HT1A agonists. Further, the instant claims are not primarily drawn to anti-dyskinetic effects, but to prolonging ON-time or reducing OFF-time. Stayte notably provides very little evidence that 5-HT1A agonists can prolong ON-time or reduce OFF-time. See page 12, right side, third para, which identifies a more recent study of sarizotan “in which no significant changes were found in dyskinesias measures but an improvement in UPDRS and “off” time was revealed”. See also pages 8-9, table 3 summarizing the clinical trial results for various 5-HT1A receptor agonists including tandospirone:
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Please also note that Stayte’s evidence (1) is limited to PD patient’s receiving levodopa, and (2) does not show that “motor fluctuations” can be prevented in said patients.
In view of the state of the art identified above, the skilled artisan would be faced with a high degree of unpredictability in preventing motor fluctuations and in identifying patients (beyond PD patients receiving levodopa therapy) who could have motor fluctuations treated, improved or prevented. Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of direction provided and working examples:
The specification discloses two examples (Examples 1 and 2) as evidence of prolongation of ON-time (i.e. treatment, improvement, or prevention of motor fluctuations).
Example 1 discloses an evaluation of tandospirone’s action of prolonging ON-time of levodopa in a PD animal model (page 182, [0131]). The experiment describes an animal model (“6-OHDA-lesioned rats”) which, when levodopa is administered, exhibits a rotational behavior. As stated by applicant “it is known that said model exhibits a rotational behavior…due to a therapeutic drug for PD…such as levodopa or dopamine receptor agonists. The usefulness of a therapeutic drug for PD can be evaluated using such rotational behavior as an indicator…prolongation in levodopa induced rotational behavior time was evaluated by using this model” (page 183, [132]).
Example 1 shows that tandospirone prolongs the duration of levodopa induced rotational behavior (“ON-time”) in comparison to the control (page 185, [0137]; FIG. 1A; FIG. 1B; FIG. 2A; FIG. 2B). Prolongation of ON-time was observed in animals receiving tandospirone either orally OR transdermally.
Example 2 shows similar prolongation of ON-time, but in a model of PD levodopa-induced dyskinesia (PD-LID). See the results discussed at page 188, [0146]; [0147] FIG. 3C; FIG. 3D; FIG. 4C; FIG. 4D; FIG. 5C; and FIG. 5D. Applicant states that prolongation of ON-time without dyskinesia was improved under transdermal tandospirone administration at safe doses; but prolongation of ON-time without dyskinesia under oral tandospirone administration was only improved at a dose where there is a risk of side effects from oral administration.
Please note that the evidence in the specification (1) is limited to PD subjects receiving levodopa, and (2) does not show that “motor fluctuations” can be prevented in said subjects.
The specification fails to provide examples where transdermally administered tandospirone was used to prevent motor fluctuations in any patient population, or to treat or improve motor fluctuations in the broader patient population (beyond PD patients receiving levodopa therapy) as set forth in the claims.
See also MPEP 2164.02 (“Compliance with the enablement requirement of 35 U.S.C. 112(a) does not turn on whether an example is disclosed … Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine, by undue experimentation, (1) how to actually prevent motor fluctuations in the claimed patient populations; and (2) which patient populations (beyond those receiving levodopa therapy for PD) would be benefited by the claimed method.
Therefore, in view of the factors discussed above, claims 30-54 are rejected as failing to comply with the enablement requirement.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 43 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The method of claim 30 recites transdermally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. Accordingly, the method of claim 30 is being interpreted as necessarily requiring that the administration is accomplished with a transdermally administered formulation. Therefore, claim 43 fails to further limit claim 30.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 30-55 are rejected under 35 U.S.C. 103 as being unpatentable over Brotchie et al. (US 20040067956 A1; published April 2004) in view of Hansen et al. (US 20150104506 A1; cited by Applicant in IDS) and in view of Onda et al. (JP H11228414 A, and English translation, cited by Applicant in IDS).
Brotchie
Brotchie discloses a method for the prevention or reduction of motor fluctuations associated with dopamine replacement therapy comprising administering to a person or animal in need of such treatment a therapeutically effective amount of a compound which enhances 5-hydroxytryptamine 1 a receptor activity, or activation (para. [0010] and claim 14).
Brotchie teaches that the compounds of the invention “enable the subject to tolerate and therefore benefit from the dopamine replacement therapy and also, surprisingly, appear to reverse the wearing-off of the efficacy of the dopamine replacement therapy. Accordingly, the compounds are able to extend duration of action of dopamine replacement therapies.” (para. [0034]). Brotchie further teaches that “compounds used according to the invention are able to surprisingly improve the “on-time” of a dopamine replacement therapy for subjects who have developed “on-off” syndrome. Accordingly the compounds are useful for producing a more stable action of dopamine replacement therapies.” (para. 0035]).
Brotchie teaches that preferred selective 5-HT1a agonists have a higher binding affinity for the 5-HT1a receptor than for the other 5-HT receptors (para. [0031]). Brotchie specifically contemplates the 5-HT1a receptor agonists: (RS)-trans-8-hydroxy-2-[N-n-propyl-N-(3′-iodo-2′-propenyl)amino]tetralin (8-OH-PIPAT); (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenylpiperazine (BP-554); 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,8-dione (Buspirone); 1-(3-chlorophenyl)-4-hexylpiperazine; (±)-5-methoxy-3-dipropylaminochroman; and (±)-8-methoxy-2-dipropylaminotetralin (para. [0023-0030]).
Brotchie contemplates administering the compounds of the invention in various forms including, powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle, liposome or any other suitable form that may be administered to a person or animal (para. 0037]).
The only differences between Brotchie and the method of claims 30 and 55 are that Brotchie does not specifically contemplate:
transdermal administration of the 5-HT1a receptor agonist; and
the specific 5-HT1a receptor agonist tandospirone.
However, tandospirone was previously known as a selective 5-HT1a receptor agonist having a higher binding affinity for the 5-HT1a receptor than for the other 5-HT receptors; and transdermal administration of tandospirone was also previously known.
Hansen
Hansen teaches (claim 32) a pharmaceutical composition comprising a selective 5-HT1A receptor agonist which can be buspirone or tandospirone. The composition is taught (claim 43) to be administered sequentially or simultaneously with levodopa. Levodopa is taught to be co-administered in claim 37. This formulation is taught (claim 39) to treat PD and movement disorders associated with PD. A specific embodiment (Example II) teaches the use of tandospirone sequentially with levodopa to treat Parkinson’s disease and reduce levodopa induced dyskinesia. See Example II and Figure 2, which shows that the intraperitoneal administration of 10 mg of tandospirone reduced AIMs after treatment with levodopa and induction of levodopa induced dyskinesia. Therefore, administering tandospirone resulted in the improvement of exacerbation of dyskinesia in response to levodopa therapy. Hansen et al. teaches (para. [0290]) a reduction of AIMs and a significant reduction of levodopa induced dyskinesia with a prolonged duration of action.
Hansen does not contemplate transdermal administration.
Onda
Onda teaches (claim 1), a transdermal composition comprising tandospirone. Onda teaches (page 3, [0002]) that tandospirone, when orally administered, produces metabolites in blood and has a short biological half-life, thus necessitating frequent dosing. Onda teaches that the preparation of tandospirone as a transdermal agent can drastically reduce the production of metabolites and sustainably maintain the blood concentration (page 3, [0004]).
In Figure 2, Examples 3-6 shows the maintenance of tandospirone in the blood up to 24 hours after transdermal administration whereas orally administered tandospirone (Comparative Example 2) is not maintained over the same period (see below):
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Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (B), it would have been obvious to modify Brotchie’s method by substituting in the specific 5-HT1a receptor agonist tandospirone in view of Hansen’s teaching that tandospirone is a 5-HT1a receptor agonist and that tandospirone prolonged the duration of action. A person having ordinary skill would have reasonably predicted success because tandospirone was previously known as an equivalent compound to buspirone, which was specifically contemplated by Brotchie.
Additionally, applying KSR example rationale (G) it would have been obvious to administer tandospirone transdermally, in view of Onda’s teaching that transdermal administration of tandospirone is superior to oral administration by reducing production of metabolites in the blood and sustainably maintaining blood concentration of tandospirone.
Therefore claims 30 and 55 are obvious over Brotchie in view of Hansen and Onda.
With respect to claims 31-34, the combination of references teaches the patient populations of these claims (patients undergoing levodopa therapy for Parkinson’s disease). Accordingly, claims 31-34 are obvious.
With respect to claims 35-42, the limitations recited in these claims are being interpreted as an intended result of a method step positively recited. As noted in MPEP 2111.04, “a ‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited’”. In the instant case, the results (reduction of OFF-time, prolongation of ON-time, sustained maintenance of a dopamine level, suppression of a rapid change in a dopamine level, etc.) are the intended results of the step of administering the claimed compound to the claimed patient population, and do not add any additional structural elements to the method of claim 30.
Please also note that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See MPEP 2112.
The prior art relied upon teaches transdermally administering tandospirone to patients undergoing levodopa therapy for PD, which is apparently the structure required to produce the claimed effects recited by claims 35-42. Morevoer, Brotchie teaches reducing OFF-time or prolonging ON-time; and Hansen teaches preventing or alleviating levodopa-induced dyskinesia and prolongation of action by tandospirone. Therefore, claims 35-42 are obvious.
With respect to claim 43, the combination of references teaches transdermal administration of tandospirone and the benefits thereof. Accordingly, claim 43 is obvious.
With respect to claims 44-47, Brotchie teaches that generally, a daily dose of between 0.01 ug/kg of body weight and 1.0 g/kg of body weight of the 5-HT1a agonist may be used for the treatment of motor fluctuations, and more preferably the daily dose is between 0.1 mg/kg of body weight and 50 mg/kg of body weight. The dosing ranges taught by Brotchie overlap with the dosing ranges recited by the instant claims. Additionally, Onda provides a teaching of different doses (1 g, 0.5 g, 0.1 g, 0.05 g) of transdermally-administered tandospirone (Examples 3-6) and the resulting blood concentrations of tandospirone over a 24-hour period (FIG. 2).
Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the dose of tandospirone administered or the drug penetration are considered result-effective variables that impacts, for example, the magnitude of the response in a subject. Absent a showing that the recited range is critical, optimizing result-effective variables is deemed routine optimization. Accordingly, claims 44-49 are obvious.
With respect to claims 48-49, the combination of references does not contemplate the transdermally applied area of the formulation. However, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the applied area of the transdermal formulation is considered a result-effective variable that impacts, for example, the dose of tandospirone delivered to the patient. Absent a showing that the recited range is critical, optimizing result-effective variables is deemed routine optimization. Accordingly, claims 48-49 are obvious.
With respect to claims 50 and 53, Onda teaches in Figure 2, Examples 5 and 6 that after 8-16 hours, the tandospirone concentration in the blood is between 1 to 15 ng/mL, and after 24 hours, the tandospirone concentration in the blood is still between 1 to 15 ng/mL. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the blood concentration of tandospirone is considered a result-effective variables that impacts, for example, the magnitude of the response in a subject. Absent a showing that the recited range is critical, optimizing result-effective variables is deemed routine optimization. Accordingly, claims 50 and 53 are obvious.
With respect to claim 51, as admitted by Applicant in the Specification (page 168, lines 8-27), “it is known that the “amount of change in striatal [11C] raclopride receptor binding from before levodopa administration to 1 hour after administration (also abbreviated as the amount of change B/1 h)” is higher in Parkinson's disease patients with motor fluctuations or dyskinesia compared to patients without motor fluctuations or dyskinesia, such as by 10% or greater or 15% or greater. If the amount of change B/1 h decreases due to drug therapy, this means that the therapy is effective on motor complications such as dyskinesia.” Applicant cited (page 168, line 4) the reference document Fernandez et al. (Brain, vol. 127, no. 12, Nov. 2004, pp. 2747–54) as evidence that the amount of change B/1 h is related to motor fluctuations or dyskinesia in PD patients receiving levodopa therapy.
While the combination of references does not specifically contemplate administering tandospirone so that an amount of change B/1h is less than 10%, it would have been obvious to apply this metric to optimize treatment effectiveness in view of both Applicant’s admission that it was known, and the Fernandez reference. Moreover, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the amount of change B/1h after administering tandospirone is considered a result-effective variables that impacts, for example, the intensity of dyskinesias or motor fluctuations in a patient. Absent a showing that the recited range is critical, optimizing result-effective variables is deemed routine optimization. Accordingly, claims 51 is obvious.
With respect to claim 52, the combination of references teaches administering tandospirone as an adjunct of levodopa. Brotchie and Hansen teach co-administering tandospirone and levodopa. Accordingly, claim 52 is obvious.
With respect to claim 54, the combination of references teaches prolonging an antiparkinsonian action ON-time (and, implicitly, reducing antiparkinsonian action OFF-time). Accordingly, claim 54 is obvious.
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.
US 10,758,535
Claims 30-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,758,535 (“the reference patent”) in view of Brotchie et al. (US 20040067956 A1; published April 2004).
The teachings of Brotchie are disclosed above and at least those teachings are incorporated herein by reference.
The reference patent recites 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.
Dependent claims recite:
wherein the transdermal administration has sustainability or is sustainably administered
wherein the tandospirone treatment or improvement comprises treatment or improvement symptom, reduction of a period of PD-LID manifestation, or a combination thereof
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
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
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
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
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
wherein the tandospirone or a pharmaceutically acceptable salt thereof is an adjunct of levodopa
wherein the sustainably administered tandospirone sustains a blood concentration sufficient for improving PD-LID symptom without exacerbating dyskinesia symptom.
The claims are therefore drawn to the administration of tandospirone to the same patient populations (i.e., PD patients receiving levodopa) over the same dosage ranges. Additionally, in view of Brotchie’s teaching that 5-HT1A receptor agonists improve the “on-time” of a dopamine replacement therapy a person having ordinary skill would have reasonably expected that the method recited in the reference patent would have treated or improved motor fluctuations in said patient populations.
Accordingly, instant claims 30-55 are obvious over the claims of the reference patent in view of Brotchie.
US 11,559,525
Claims 30-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11,559,525 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite a method for treating, improving, or delaying progression of dyskinesia in a subject, comprising transdermally or subcutaneously administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or the pharmaceutically acceptable salt 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 the pharmaceutically acceptable salt thereof.
Dependent claims 22-24 recite:
wherein the method further improves motor fluctuations in the subject;
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;
wherein treatment, improvement, or delay of progression 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.
Additional dependent claims recite:
wherein the subject is suffering from Parkinson's disease:
wherein the subject is subject to a drug therapy of Parkinson's disease
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, dopamine replacement therapies and Parkinson's disease adjunct;
wherein dopamine amount in striatal synaptic cleft of the subject is sustainably maintained and/or suppressing rapid changes;
wherein a levodopa-evoked synaptic dopamine fluxes in a striatum of the subject using 11C-raclopride Positron Emission Tomography (PET) test is sustainably maintained, and/or suppressing rapid changes and/or intermittent domain receptor stimulation is suppressed;
wherein the transdermal or subcutaneous administration comprises transdermal administration;
wherein the treatment, improvement, or delay of progression of dyskinesia comprises improvement, or delay of progression of a dyskinesia symptom, reduction of a period of PD-LID manifestation, or a combination thereof;
wherein a drug dosage of the tandospirone or the pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as a free form of tandospirone;
wherein an amount of drug penetration for the tandospirone or the pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation, and a total applied area per dose is 1 to 100 cm2;
wherein the human blood (plasma) tandospirone concentration is 1 to 12 ng/mL;
wherein the human blood (plasma) tandospirone concentration is 2 to 10 ng/mL;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is an adjunct of levodopa;
wherein the tandospirone or the 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, 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 or the pharmaceutically acceptable salt thereof;
wherein the tandospirone or the 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, 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 or the pharmaceutically acceptable salt thereof;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is administered so that an amount of change in striatal [11C] raclopride receptor binding from before levodopa administration to 1 hour after administration (amount of change B/1 h) is less than 10% after administering the tandospirone or a pharmaceutically acceptable salt thereof.
The claims are therefore drawn to the administration of tandospirone to the same patient populations (i.e., PD patients receiving levodopa) over the same dosage ranges to treat, improve, or delay progression of motor fluctuations in the subject.
Accordingly, the instant claims are unpatentable over claims 1-29 of the reference patent.
US 11,628,169
Claims 30-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,628,169 (“the reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference patent recite a method of treating or improving motor fluctuations in Parkinson's disease, wherein the motor fluctuations are selected from the group consisting of wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon and a combination thereof, wherein the method comprises transdermally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject in need thereof.
Dependent claims recite:
wherein the subject is undergoing drug therapy for Parkinson's disease;
wherein the subject is undergoing drug therapy selected from the group consisting of drug therapy for Parkinson's disease using a levodopa containing formulation, a levodopa metabolite inhibitor, or a dopamine receptor agonist and therapy using an adjunct agent for Parkinson's disease;
wherein the subject is undergoing dopamine replacement therapy for Parkinson's disease;
wherein the subject is undergoing levodopa therapy for Parkinson's disease;
wherein the method does not cause troublesome dyskinesia;
wherein the method does not exacerbate a dyskinesia symptom in Parkinson's disease;
wherein the method does not exacerbate a levodopa induced dyskinesia (PD-LID) symptom;
wherein the method does not cause a rebound symptom of levodopa induced dyskinesia (PD-LID);
wherein the method does not cause a troublesome dyskinesia symptom;
wherein the administration is accomplished with a transdermally administered formulation;
wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as a free form of tandospirone;
wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as a free form of tandospirone;
wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as a free form of tandospirone;
wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt thereof is 1 to 60 mg per day as a free form of tandospirone;
wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation, and a total applied area per dose is 1 to 100 cm2;
wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation, and a total applied area per dose is 9 to 60 cm2;
wherein the tandospirone or a pharmaceutically acceptable salt 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 thereof;
wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that an amount of change in striatal [11C] raclopride receptor binding from before levodopa administration to 1 hour after administration (amount of change B/1 h) after administering the tandospirone or a pharmaceutically acceptable salt thereof is less than 10%;
wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as an adjunct of levodopa;
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, 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 or a pharmaceutically acceptable salt thereof;
wherein the size of the formulation ranges from 1 cm2 to 160 cm2;
wherein the size of the formulation ranges from 9 cm2 to 160 cm2;
wherein the method comprises reducing OFF time without troublesome dyskinesia and/or without exacerbating a dyskinesia symptom in Parkinson's disease.
The claims are therefore drawn to the administration of tandospirone to the same patient populations (i.e., PD patients receiving levodopa) over the same dosage ranges to treat or improve motor fluctuations in the subject.
Accordingly, the instant claims are unpatentable over claims 1-29 of the reference patent.
Claims 30-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/084,367 (“the reference application”).
The reference application recites 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 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.
Dependent claims 26-28 recite:
wherein the method further improves motor fluctuations in the subject;
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;
wherein treatment, improvement, or delay of progression 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.
Additional dependent claims recite:
wherein the subject is suffering from Parkinson's disease:
wherein the subject is subject to a drug therapy of Parkinson's disease
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;
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, a therapy with levodopa metabolism enzyme inhibitor and a dopamine receptor agonist;
wherein dopamine amount in striatal synaptic cleft of the subject is sustainably maintained and/or suppressing rapid changes;
wherein the administration is performed without inducing rebound symptoms in the subject;
wherein a levodopa-evoked synaptic dopamine fluxes in a striatum of the subject using 11C-raclopride Positron Emission Tomography (PET) test is sustainably maintained, and/or suppressing rapid changes and/or intermittent domain receptor stimulation is suppressed;
wherein the parenteral administration comprises transdermal administration;
wherein the treatment, improvement, delay of progression, or prevention improves dyskinesia without a rebound symptom;
wherein the treatment, improvement, or delay of progression of dyskinesia comprises improvement, or delay of progression of a dyskinesia symptom, reduction of a period of PD-LID manifestation, or a combination thereof;
wherein a drug dosage of the tandospirone or the pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as a free form of tandospirone;
wherein an amount of drug penetration for the tandospirone or the pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is provided as a transdermally administered formulation, and a total applied area per dose is 1 to 100 cm2;
wherein the human blood (plasma) tandospirone concentration is 1 to 12 ng/mL;
wherein the human blood (plasma) tandospirone concentration is 2 to 10 ng/mL;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is an adjunct of levodopa;
wherein the tandospirone or the 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, 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 or the pharmaceutically acceptable salt thereof;
wherein the tandospirone or the 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, 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 or the pharmaceutically acceptable salt thereof;
wherein the tandospirone or the pharmaceutically acceptable salt thereof is admini