DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed 11/16/2022, is a 371 filing of PCT/AU2021/050662, filed 06/24/2021, which claims foreign priority to AU2020902131, filed 06/25/2020.
Amendments and Claim Status
The following amendment filed on 02/12/2016 is acknowledged and entered.
Claim 1 is amended;
Claim 25 is cancelled;
Claim 4 remains withdrawn according to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species;
Claims 1-3, 5-24, 26, and 27 are being examined on the merits.
Claims 1-24, 26, and 27 are pending.
Claim Interpretation
This application includes the claim limitation of claim 1, which recites “A method for treating or preventing organophosphorus poisoning in a subject comprising administering an effective amount of a sustained-release aqueous intranasal formulation to a subject”…“wherein rivastigmine…Is the sole active agent in the formulation”.
According to the MPEP, the language “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. see MPEP § 2111.03(I)). The claims are subject to the following interpretation:
Under the broadest reasonable interpretation (BRI) as set forth in MPEP 2111, the recitation of “comprising” is interpreted as including un-recited elements or steps.
Rivastigmine is interpreted as being the only active agent within the formulation. The method however may encompass unrecited elements or method steps.
Response to arguments
Applicant’s arguments filed 02/12/2016 with respect to the objection to the specification and claim rejections under 35 U.S.C. §§ 112(a) and 103 have been fully considered.
With respect to the objection to the specification for the inclusion of a resolution two-dimensional drawing of rivastigmine, the amendment specification filed 02/12/2026 is satisfactory sufficient to overcome the objection.
With respect to the rejection of claims 1-3, 5-24, 26, and 27 under 35 U.S.C. § 112 (a) as failing to comply with the written description requirement, Applicant’s arguments have been fully considered and are found to be persuasive. Accordingly, the previous rejection under 35 U.S.C. § 112 (a) is hereby withdrawn.
With respect to the rejection of claims 1-3, 5-24, 26 and 27 under 35 U.S.C. § 103 as being unpatentable over Volvovitz (US 20090048234 A1, published February 19, 2009) in view of Morgan and Soh, the arguments made by applicant are herein addressed as follows.
Applicant argues that Volvovitz teaches a synergistic combination of an AChE inhibitor with an anticholinergic compound, which is a teaching away from using rivastigmine alone to treat OP poisoning.
Applicant’s argument is found unpersuasive because “comprising” as recited in the preamble of instant claim 1 does not exclude additional components or steps. As a matter of ordinary claim construction, “comprising” is an open-ended transitional phrase, and does not exclude the presence of additional components, according to MPEP § 2111.03. A method that includes administration of rivastigmine together with an anticholinergic compound as taught by Volvovitz is encompassed by claim 1 as recited. The claim as written encompasses the use of a composition that merely includes rivastigmine as the sole active agent within the formulation. The claimed method does not affirmatively exclude the administration of any other active agent within the open claim language of the method. That is, claim 1 only requires the administration of a formulation with rivastigmine as the only active ingredient but does not exclude additional steps which allow for the administration of other compositions with active ingredients—which would be the same as administration of a combination as taught by Volvovitz. Furthermore, Volvovitz teaches the active agents can be administered separately by different routes of administration (paragraphs [0043-0046]). As such, the prior art encompasses administration of a formulation with rivastigmine as the only active ingredient which can be administered by nasal inhalation, with another active separately administered by a different administration route, falling squarely within the scope of the instant claims. Furthermore, even if the compounds are administered separately by different routes of administration, which is allowed for by the current claims, synergy as taught in Volvovitz can still be achieved and thus Applicant’s argument that synergy teaches away from the instant invention is found not persuasive.
Applicant argues that Volvovitz fails to teach the specific aqueous intranasal sustained-release formulation, specific percentages of rivastigmine, thickening agent, and pH ranges encompassed by claim 1.
Applicant’s argument is found unpersuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). A person having ordinary skill in the art would have been directly motivated to modify the teachings of Volvovitz in the use of the acetylcholinesterase inhibitor rivastigmine in the treatment of organophosphorus poisoning by soman following the teachings of Morgan and Soh, who disclose a clinically validated intranasal sustained-release formulation of rivastigmine—in order to achieve a more effective, non-invasive, and sustained delivery of rivastigmine. The shared cholinergic mechanistic rationale between organophosphate toxicity by soman and neurodegeneration in Alzheimer’s and Parkinson’s disease coupled with the demonstrated ability of the formulation taught by Morgan and Soh to provide stable central acetylcholinesterase inhibition with reduced systemic side effects, provides a clear expectation of success than adapting a specific formulation with demonstrated success would predictably improve efficacy, safety, and compliance in managing organophosphorus poisoning. Furthermore, Volvovitz states within the disclosure a goal of maintaining continuous cholinergic modulation (paragraph [0050]). This provides direct motivation to use the sustained-release rivastigmine composition taught by Morgan and Soh as a neuroprotective countermeasure for organophosphate toxicity. Thus, the teaching of the references taken together renders the instant claims obvious.
Finally, applicant argues that there is no motivation to combine Volvovitz with the teachings of Morgan and Soh, because Volvovitz teaches a combination of active agents, while Morgan and Soh teach only rivastigmine alone. Therefore, a person having ordinary skill in the art would have no reason to apply the intranasal sustained-release formulation of Morgan and Soh to the combination-focused teachings of Volvovitz.
Applicant’s argument is found unpersuasive because Volvovitz (paragraphs [0043-0046] explicitly teach that the specific formulation and route of administration depend on the condition being treated and that the compounds can be administered adjunctively, and that formulations can comprise combinations, or single compounds depending on the indication (paragraph [0046])—directly supplying motivation to solely administer rivastigmine in a separate formulation from the other agents. Volvovitz teaches the compounds of the invention can be administered via the same or via a different mode of administration, for example, a huperzine compound, pharmaceutically acceptable salt or hydrate can be administered transdermally and caramiphen, pharmaceutically acceptable salt or hydrate can be administered orally [0045]. Additionally, the same compound or class of compound can be administered by two different routes [0045]. Thus the teachings of Volvovitz allows for the separate administration of the compounds and thus the rivastigmine may be formulated in a separate formulation which motivates an ordinary skilled artisan to formulate rivastigmine based on the teachings of Morgan and Soh which teaches intranasal formulations of rivastigmine having improved properties.
For all the reasons outlined above, Applicant has failed to overcome the prima facie case of obviousness case and therefore the rejection under 35 U.S.C. § 103(a) is maintained.
With respect to the rejection of claims 1-3, 5-24, 26, and 27 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,471,040 B2 in view of Volvovitz (see earlier citation), in further view of Morgan and Soh (see earlier citation), Applicant has not submitted arguments to consider. Furthermore, the amendment to claim 1 does not overcome the grounds of the double patenting rejection due to the open claim language.
As such, Applicant has failed to overcome double patenting rejection. The rejection is therefore maintained.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 1-3, 5-24, 26 and 27 are rejected under 35 U.S.C. § 103 as being unpatentable over Volvovitz (US 20090048234 A1, published February 19, 2009) in view of Morgan and Soh (British Journal of Clinical Pharmacology, Volume 83, pages 510–516, published Oct. 26, 2016).
The instant claims are drawn to a method for treating or preventing organophosphorus poisoning in a subject comprising administering a sustained-release aqueous intranasal formulation comprising rivastigmine (0.5-15 wt%), pH modifying agent (maintaining pH between 3-6), and a thickening agent (0.25-2 wt%). Organophosphorus poisoning is further is caused by an organophosphorus nerve agent, elected in the instant case to be soman. The method further comprises the administration of an additional therapeutic agent, elected in the instant case to be pyridostigmine. The method further comprises the administration of a sensory agent and particular pharmacokinetic outcomes.
Volvovitz teaches compositions and methods for preventing, treating, or reversing neuronal dysfunction resulting from exposure to organophosphate nerve agents (Abstract, see instant claim 1). The disclosure teaches wherein soman is one of the most widely produced organophosphorus nerve agents (paragraph [0106], see instant claims 2 and 3). Volvovitz teaches a composition comprising the acetylcholinesterase inhibitor, rivastigmine (claims 2 and 12, see instant claim 1). This composition is used in a method for prevention, treatment, or reversal of symptoms or neurodegenerative changes (claims 22-26, paragraph [0102], see instant claim 1) as well as human central nervous system injury resulting from both Parkinson’s and Alzheimer’s diseases (paragraph [0002]). Nasal methods of administration are cited by the disclosure as a viable methods to minister the prior art composition (paragraph [0043], see instant claim 1). The prior art also teaches long-acting formulations wherein suitable polymeric or hydrophobic materials are incorporated in order to improve delivery of the active ingredients (paragraph [0050], see instant claim 1). One of the acetylcholinesterase inhibitors used in the prior art is taught to be rivastigmine (claim 2, see instant claim 1). The composition is taught to be administered to a healthy young, middle-aged, or elderly subject (paragraph [0102], see instant claims 5-7). Rivastigmine dosages are disclosed in the range of 1.0 μg/kg/day to 25,000 μg/kg/day (paragraph [0089])—which for a 70 kg human subject is equivalent to 0.07 mg/day-1,750 mg/day, overlapping with the instantly claimed ranges (see instant claims 1, 14-16). Tables 5 lists embodiments of compositions which were administered to humans, and Volvovitz teaches wherein the acetylcholinesterase inhibitors active ingredient may be substituted for 0.2 mg/kg rivastigmine, which is equivalent to 14 mg rivastigmine in a 70 kg human. Within Table 7, specific embodiments are listed wherein rivastigmine may be 75 μg/kg, which for a 70 kg person is equivalent to 5.25 mg (see instant claims 14-16). A number of excipients are cited including gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP), as well as a number of starches (paragraph [0047], see instant claim 10). Volvovitz further teaches that the oral antidote enhancer, pyridostigmine, alone provides incomplete protection because it does not cross the blood brain barrier (paragraph [0017]). Volvovitz teaches wherein pyridostigmine provides no protection by itself, but the combination with other acetylcholinesterase inhibitors enhances efficacy against soman (paragraph [0113], see instant claims 2 and 3). The teachings specifically cite the synergistic action of combinations of active ingredients (paragraphs [0018-0019], see instant claims 13 and 27). Finally, the disclosure also teaches the combination of active ingredients may reduce side effects otherwise expected from individual compounds (paragraphs [0018, 0020], see instant claim 24).
Although the teachings of Volvovitz overlap with the instantly claimed method of treating or preventing organophosphorus poisoning by soman in healthy human subjects, as well as instantly claimed ranges of rivastigmine, and combination with pyridostigmine, Volvovitz fails to teach a specific aqueous intranasal sustained-release rivastigmine formulation with the claimed percentages of rivastigmine and thickening agent. Volvovitz also fails to teach specific pH ranges at which the formulation should be maintained. The instantly claimed sensory excipients are also lacking in the disclosure by Volvovitz. Finally, Volvovitz fails to teach specific human intranasal pharmacokinetic performance endpoints achieved (Cmax,Tmax, AUC values), or any comparative “reduced side effects” of the intranasal versus oral composition.
The deficiencies of Volvovitz are remedied by Morgan and Soh, who teach a specific formulation which renders obvious the instant claims, and supply pharmacokinetic and clinical evidence for intranasal rivastigmine delivery. The disclosure by Morgan and Soh is centered on the use of a formulation to in healthy elderly adults (page 511, see instant claims 5-7) specifically used for the treatment of dementia associated with Alzheimer’s and Parkinson’s disease (Abstract, page 510). Morgan and Soh disclose a precisely defined aqueous intranasal formulation containing 2.5 % w/v rivastigmine tartrate (see instant claims 1 and 8), 1% w/v polyvinylpyrrolidone as a thickening agent, 0.055% w/v citric acid as a pH modifying agent (see instant claim 1, 9), and ethanol 10% w/v and benzyl alcohol 0.65% as sensory agents (see instant claims 11 and 12), which overlaps with the instantly claimed composition used in a method of treating organophosphorus poisoning. This intranasal formulation is adjusted to a pH of 3.6 (page 512, see instant claim 1) thereby arriving at the instantly claimed composition used in a method of treatment. Morgan and Soh further describe human dosing of 3.126 mg of rivastigmine in healthy elderly subjects (Abstract, see instant claims 5 and 6), yielding the pharmacokinetic parameters which directly correspond to the claimed sustained-release characteristics absent from Volvovitz (Table 2 of the disclosure, reproduced as Table 1, below).
Table 1. Noncompartmental pharmacokinetic parameters of rivastigmine and NAP226–90 after administration of 3.126 mg rivastigmine nasal spray (one spray each nostril), n = 8
PNG
media_image1.png
266
695
media_image1.png
Greyscale
According to the table, the maximum rivastigmine plasma concentration (Cmax) was 6.9 ng/ml (see instant claims 17 and 18), and the time to maximum plasma concentration was 1.1 hour (see instant claims 19 and 20). The NAP226–90 to rivastigmine AUC0–∞ ratio was 0.78 ± 0.9 (see instant claims 21 and 22), with an average AUC value of 22.6 ng.h/ml (see instant claim 23). Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose (Abstract, see instant claim 24). Additionally, the disclosure confirms acetylcholinesterase inhibition comparable to oral and transdermal delivery (page 514) and recipients reported only mild, transient nasal irritation with no nausea vomiting or diarrhea (page 514 see instant claim 24). Collectively, the teachings by Morgan and Soh provide the empirical formulation detail, pharmacokinetic validation, and safety confirmation that Volvovitz lacks, enabling the skilled artisan to adapt the sustained-release aqueous intranasal rivastigmine formulation for use in a method of treating and preventing organophosphorus poisoning by soman.
A person of ordinary skill in the art, prior to the filing date of the instant claims would have been directly motivated to modify the teachings of Volvovitz in the use of the acetylcholinesterase inhibitor rivastigmine in the treatment of organophosphorus poisoning by soman following the teachings of Morgan and Soh, who disclose a clinically validated intranasal sustained-release formulation of rivastigmine—in order to achieve a more effective, noninvasive, and sustained delivery of rivastigmine. The shared cholinergic mechanistic rationale between organophosphate toxicity by soman and neurodegeneration in Alzheimer’s and Parkinson’s disease coupled with the demonstrated ability of the formulation taught by Morgan and Soh to provide stable central acetylcholinesterase inhibition with reduced systemic side effects, provides a clear expectation of success than adapting a specific formulation with demonstrated success would predictably improve efficacy, safety, and compliance in managing organophosphorus poisoning. Furthermore, Volvovitz states within the disclosure a goal of maintaining continuous cholinergic modulation (paragraph [0050]). This provides direct motivation to use the sustained-release rivastigmine composition taught by Morgan and Soh as a neuroprotective countermeasure for organophosphate toxicity.
Regarding claims 13 and 27, Morgan and Soh fail to teach a method of treatment further comprising the administration of pyridostigmine. However, a person of ordinary skill in the art would have found it obvious to further administer pyridostigmine, as both pyridostigmine and rivastigmine are used for the common purpose of protection against soman-induced acetylcholinesterase inhibition, as taught by Volvovitz (claim 2 and paragraphs [0017 and 0113]). According to MPEP 2144.06 (I), combining equivalents known for the same purpose is rendered obvious. The courts have said,
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
Therefore, a person having ordinary skill in the art would have found it prima facie obvious to combine rivastigmine with pyridostigmine following the teachings of Volvovitz, as they are both commonly used for protection against soman-induced acetylcholinesterase inhibition—yielding complementary and predictable neuroprotective benefits.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-24, 26, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,471,040 B2 in view of Volvovitz (see earlier citation), in further view of Morgan and Soh (see earlier citation). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented method of treating a neurodegenerative disease in a mammal comprising a sustained-release aqueous intranasal formulation (see claims 3 and 1), is directly applicable to organophosphorus poisoning by soman, according to the teachings of Volvovitz.
Although the patented case recites a method to treat Alzheimer’s and Parkinson’s disease and a nearly identical composition administered, it lacks the instantly claimed method of treating organophosphorus poisoning. The patented case also lacks specific pharmacokinetic parameters found in the instant claims.
These deficiencies are remedied by Volvovitz, who teaches wherein Alzheimer's disease, Parkinson's disease, and organophosphorus poisoning overlap in the relation to their common mechanism of acetylcholinesterase receptor dysfunction (Abstract). More specifically, soman is taught by Volvovitz to be one of the most widely produced organophosphorus nerve agents (paragraph [0106]). The method and composition taught by Volvovitz further comprises the use of pyridostigmine (paragraph [0017]), in order to reduce side effects otherwise expected from the use of individual active ingredients (paragraphs [0018, 0020]).
The deficiencies of the patented case in teaching the particular pharmacokinetic parameters of the instant claims are remedied by Morgan and Soh, who teach a method of treating Alzheimer’s in Parkinson’s disease with a composition that overlaps with the scope of the instant claims (Abstract). More specifically, the instantly claimed pharmacokinetic parameters (Cmax,Tmax, AUC values) can be found in the earlier included Table 1. The disclosure provides strong evidentiary support that the composition used successfully treats acetylcholinesterase dysfunction.
As such, person of ordinary skill in the art would have found it obvious to apply the patented composition to a method of treating organophosphorus poisoning as described by Volvovitz, as organophosphorus poisoning, Parkinson’s, and Alzheimer’s disease overlap in their acetylcholinesterase dysfunction mechanisms. A person of ordinary skill in the art would have found it obvious to incorporate the pharmacokinetic parameters associated with the administration of a composition with demonstrated success in treating acetylcholinesterase dysfunction following the teachings of Morgan and Soh, in order to arrive at the instant claims.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR § 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR § 1.17(a)) pursuant to 37 CFR § 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call +1 (800) 786-9199 (IN USA OR CANADA) or +1 (571) 272-1000.
/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
Prosecution Insights