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 .
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.
Current Status of 17/899,107
This Office Action is responsive to the amended claims received 12 August 2026.
Claims 1-4, 6-8, 10-17, 21-28, 51-52, and 57-59 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent application 63/239,059 (filed 31 August 2021) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Response to Amendments
The 35 U.S.C. 112 rejection to the claims, present in the previous office action, is hereby withdrawn due to Applicant’s amendments.
The 35 U.S.C. 102(a)(1) rejections to the claims, present in the previous office action, are hereby withdrawn due to Applicant’s amendments and arguments.
The 35 U.S.C. 103 rejections to the claims, present in the previous office action, are maintained herein, but they are amended as necessitated by Applicant’s amendments.
Response to Arguments
Applicant's arguments received 12 August 2026 have been fully considered.
Applicant argues that claim 18 was not rejected under 35 USC 102 in the previous action. Applicant argues that the limitation that has now been added to claim 1, previously present in claim 18, would be understood to indicate that the patient would have a lower chance of having acute pain from surgery transition to chronic pain as a result of the amitifadine administration.
Applicant argues that neither BYMASTER nor LACOUTURE teach beginning administration of amitifadine in a 1-3 week pre-operative window before surgery and continuing administration 4-52 weeks after surgery. Applicant also argues that they do not teach the acute to chronic pain transition that is instantly claimed. Applicant argues that BYMASTER doesn’t mention persistent post-surgical pain. Applicant argues that the drugs and dosing time periods of LACOUTURE are different from those that are instantly claimed. Applicant argues that claim 1 requires a specific population of patients that will have surgery in the near future and benefit from administration of the drug after surgery. Applicant argues that the Examiner’s reasoning based upon BYMASTER is incorrect. Applicant argues specifically that a patient being prescribed amitifadine and then requiring surgery would “not necessarily” be 1-3 weeks before surgery when beginning their amitifadine administration, instead surgery could be “weeks, months, or years” later. Applicant argues that the Examiner has not provided a sufficient explanation for the rejections of the instant claims.
The Examiner has withdrawn the previous rejections under 35 USC 102. BYMASTER clearly teaches the use of the compositions therein to treat or prevent acute pain that progresses on to chronic pain, wherein the pain may be pain from surgery (paragraph [0056]). The acute phase of the pain may be expected to last no more than 3 months, and the chronic phase of the pain may be expected to last more than 6 months according to BYMASTER (paragraph [0056]). This appears to teach the prevention of the transition from acute to persistent post-surgical pain to the Examiner, although using slightly different wording.
One of ordinary skill in the art, reading the teachings of BYMASTER before the instant filing date, was directly taught to administer amitifadine to a patient undergoing surgery as a preventative therapeutic. This clearly taught the artisan to begin administration before the surgery itself. And as shown above, the artisan is taught to administer the amitifadine for 6 months following the surgery. BYMASTER also clearly teaches the use of the therapies therein to treat chronic pain due to osteoarthritis (paragraph [0057]). One of ordinary skill in the art, reading the teachings of BYMASTER, before the instant filing date, would have been directly taught to begin administering an osteoarthritis patient amitifadine at any time when they are experiencing osteoarthritis pain. They also would have been directly taught that the administration of amitifadine would be useful to prevent acute pain from surgery that may progress on to chronic pain.
The only limitation in instant claim 1 that is not directly taught by BYMASTER is the specific time period of 1-3 weeks before surgery. Would the artisan have thought it obvious, based upon the teachings of BYMASTER, to begin prescribing amitifadine 1, 2, or 3 weeks before surgery to a patient presenting with osteoarthritis pain? It is the Examiner’s determination that this would have been obvious to them, and the artisan would have expected success when doing so, because it is directly taught to be beneficial by BYMASTER.
The Examiner agrees that there are differences between BYMASTER and LACOUTURE. It is the Examiner’s determination that it would have been obvious to combine the therapy of BYMASTER with that of LACOUTURE, because they both teach methods of treating pain related to surgery.
Claim Interpretation
The Examiner is interpreting the phrase “substantially daily”, within the instant claims, to indicate that administration occurs at least once within several days, and on any days that administration is performed at least once, administration may be performed many times during that day. Paragraph [0017] of the instant specification states that “substantially daily” refers to “a brief cessation of treatment” and then provides an example.
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.
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, 6-8, 10-11, 21-22, 24-25, 27-28, 51-52, 57, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over:
BYMASTER (US 2015/0005359 A1, Publication Date 1 January 2015)
as evidenced by:
HAGEN (US 2007/0043100 A1, Publication Date 22 February 2007).
BYMASTER teaches a method of treating pain through the administration of (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, being identical to the instantly claimed amitifadine, or a pharmaceutically acceptable salt thereof (claim 1 of BYMASTER). BYMASTER specifically teaches the once daily administration of amitifadine in paragraphs [0137] and [0252] therein. Twice daily administration of amitifadine is taught by BYMASTER in paragraph [0079] therein. Paragraph [0057] of BYMASTER teaches that compounds therein can be used to treat or prevent “chronic pain”, which is pain that lasts more than 6 months and includes osteoarthritis, neuropathies, non-neuropathic pain, postmastectomy pain, musculoskeletal pain, low back pain, and fibromyalgia pain. Paragraph [0056] of BYMASTER teaches that compounds therein can be used to treat or prevent “acute pain”, which is pain that typically does not last more than 3 months and includes pain from surgery, a headache, a bone fracture, or bladder disfunction pain. Paragraph [0056] of BYMASTER also teaches that the compounds therein can be used to prevent or treat acute pain, that may be caused by surgery, and which may progress on to subacute or chronic pain, being 3-6 months or more than 6 months. Clearly, prevention of pain from surgery requires administration of the drug therein before the surgery takes place. Paragraph [0058] of BYMASTER teaches that neuropathic pain includes post-herpetic neuralgia.
BYMASTER teaches that amitifadine was successfully administered orally in rats (paragraph [0031]). BYMASTER teaches that the pharmaceutical compounds therein may be administered in a range of 10 to 25 mg in paragraph [0252]. BYMASTER also teaches that the pharmaceutical compounds therein may be administered over weeks or months (paragraph [0252]). Claim 9 of BYMASTER teaches that the amitifadine being administered is in the form of the hydrochloride salt. BYMASTER teaches that the compounds therein may be administered along with other therapeutic agents, such as opioids or N-methyl-D-aspartate receptor (NMDA) antagonists (paragraph [0253]). Claim 11 of BYMASTER teaches that the amitifadine administered in the method therein is Polymorph A.
BYMASTER teaches that the compounds therein, being amitifadine and salts thereof, are administered once or twice daily and are capable of treating or preventing: chronic pain that lasts more than 6 months and acute pain that lasts 3 months or less. BYMASTER also specifically teaches that amitifadine can be administered for the treatment of chronic osteoarthritis pain and acute pain resulting from surgery. One of ordinary skill in the art would have read the teachings of BYMASTER and reasonably envisaged a method of treating both chronic osteoarthritis pain and acute pain from surgery for a single patient who may need both treatments. BYMASTER teaches the treatment of chronic pain from osteoarthritis lasting more than 6 months, and BYMASTER teaches the treatment of acute pain from surgery lasting less than 3 months, wherein the treatment for chronic pain could simply be continued as a patient requires surgery. Persistent post-surgical pain appears to be synonymous with acute pain from surgery progressing to subacute or chronic pain after the surgery, as discussed by BYMASTER.
BYMASTER teaches the administration of amitifadine before surgery and for months after surgery, but does not clearly specify the 1-3 weeks required by instant claim 1.
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, that a patient being treated for chronic osteoarthritis pain and needing surgery could be treated with amitifadine to treat the pain from their osteoarthritis and the surgery at any point before the surgery, and the artisan would have immediately envisaged that point to be at least all time points less than 6 months, including 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, and 5 months before the surgery. The artisan would have expected success in this administration, because BYMASTER clearly teaches amitifadine to be useful to treat: a patient having osteoarthritis pain, and a patient who will undergo surgery in the future to prevent acute pain caused by the surgery that may progress on to be chronic pain.
Regarding claim 25: Paragraph [0050] of BYMASTER teaches that heavy drinkers, who are taught to be treated by administering amitifadine therein, may be human males or human females who drink more than a specified amount. A method of treating a human female who drinks heavily, as taught by BYMASTER, reads on the adult female of instant claim 25.
Regarding claim 52: Paragraph [0045] of BYMASTER teaches that (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (amitifadine) “exists in at least three polymorphic forms, labeled polymorphs A, B, and C, as disclosed in U.S. patent application Ser. Nos. 11/205,956…”. US application 11/205,956 was published as HAGEN, cited above. HAGEN provides evidence that “polymorph A”, referred to by BYMASTER, includes various peaks and specifically a °2θ peak of 17.14 (HAGEN Table 1 on Pg. 2).
Regarding claim 57: Claim 40 of BYMASTER, being dependent upon claim 24 therein, teaches a method of treating a patient’s pain using amitifadine, wherein the patient is a codeine non-responder. This claim has no teaching related to the patient’s relationship to alcohol. Therefore, one of ordinary skill in the art would read claim 40 of BYMASTER to include patients without a recent history of alcohol abuse. Additionally, paragraph [0034] of BYMASTER teaches that, in some embodiments, the human patient is a heavy drinker, which logically indicates that, in other embodiments, the human patient is not.
Regarding claim 59: Paragraph [0071] of BYMASTER teaches administration of amitifadine at a dosage of 75 mg to 1000 mg. Paragraph [0250] of BYMASTER teaches administration of oral dosage forms of amitifadine.
Regarding claim 21: BYMASTER teaches a method for the treatment of pain, which nearly all humans experience. Instant claim 21 is limited to patients having “pain catastrophization”, which is defined therein as an increased pain intensity, increased disability, difficulty disengaging from pain, or a belief that pain will intensify and will not be decreased. These are differences from a normal population of human patients that are only differences in degree. The prior art teaches that amitifadine is useful to treat patients that are experiencing pain, and instant claim 21 would have been obvious to one of skill in the art as it claims the treatment of patients experiencing a higher degree of pain. In other words, BYMASTER teaches the treatment of pain generally, and does not exclude higher intensity pain. See MPEP 2144.05(II)(A).
Regarding claim 22 and 24: BYMASTER specifically teaches a method of administering amitifadine along with a tricyclic antidepressant (paragraph [0147]). As antidepressants are prescribed to treat depression and the symptoms thereof (including anhedonia), it would have been immediately obvious to one of ordinary skill in the art that this particular method, taught by BYMASTER, would have been beneficial to patients experiencing pain and depression, and the symptoms thereof.
Claims 1, 6-8, 10-12, 21-22, 24-25, 27-28, 51-52, 57, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over:
BYMASTER (US 2015/0005359 A1, Publication Date 1 January 2015)
in view of:
WHITE (White, R.I.; Pollak, J.; Persing, J.; et al. “Long-Term Outcome of Embolotherapy and Surgery for High-Flow Extremity Arteriovenous Malformations” Journal of Vascular and Interventional Radiology, Volume 11, Issue 10, November–December 2000, Pages 1285-1295).
Teachings of BYMASTER are described above.
Regarding claim 12: BYMASTER teaches that pain from surgery may be treated by the methods therein in paragraph [0056], and teaches that pain from arteriovenous malformation (a cardiovascular condition) may be treated in paragraph [0057].
WHITE teaches that four patients with lower extremity AVM (arteriovenous malformations, defined on Pg. 1285) had undergone surgery to treat the arteriovenous malformation (Pg. 1287, 3rd paragraph). WHITE also teaches that pain was symptomatic of AVM in two patients with AVM near the heel (Pg. 1287, 4th paragraph).
One of ordinary skill in the art, reading the teachings of BYMASTER would have sought to better understand arteriovenous malformation, and would have found the teachings of WHITE. WHITE teaches that surgery is a known treatment for AVM. It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to treat pain in patients having AVM with amitifadine (as taught by BYMASTER), and to continue treating their pain when they undergo surgery for the treatment AVM, being a type of cardiovascular surgery. The artisan would have expected success from this process, because it was likely that amitifadine, being useful for AVM pain, would have been useful for the closely related pain due to surgical AVM treatment.
Claims 1, 6-8, 10-11, 13-16, 21-22, 24-28, 51-52, and 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over:
BYMASTER (US 2015/0005359 A1, Publication Date 1 January 2015)
in view of:
LACOUTURE (WO 2013/013076 A1, International Publication Date 24 January 2013).
Teachings of BYMASTER are described above.
Regarding claims 13-16, 26, and 58: BYMASTER teaches that pain from surgery may be treated by the methods therein in paragraph [0056], and teaches that pain from osteoarthritis may be treated in paragraph [0057]. BYMASTER teaches that the compounds therein may be administered along with other therapeutic agents (paragraph [0253]).
LACOUTURE teaches a method of treating post-operative pain, stemming from orthopedic surgery, using a combination of a diclofenac compound and a beta-cyclodextrin compound (claim 1). LACOUTURE teaches that a “total knee” surgery is a species of orthopedic surgery therein (Pg. 14, Ln. 6-8), and it is clear throughout the specification that this indicates knee replacement, such as in example 1 (Pg. 20, Ln. 32-33). LACOUTURE teaches that pre-menopausal women took part in the study therein (Pg. 81, Ln 16-17).
One of ordinary skill in the art, reading the teachings of BYMASTER, would have sought to understand other methods for treating pain, and would have found the teachings of LACOUTURE. It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to combine the method of treating pain from surgery using amitifadine (taught by BYMASTER), with the method and composition for treating post-operative pain related to a total knee replacement (as taught by LACOUTURE), to improve the efficacy of the pain treatment. The artisan would have expected success with this combination, because both the method of BYMASTER and the method of LACOUTURE provide compositions for the treatment of pain related to surgery.
This is an example of combining equivalent therapeutic agents known to be useful for the same purpose. “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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
Claims 1-4, 6-8, 10-11, 17, 21-25, 27-28, 51-52, 57, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over:
BYMASTER (US 2015/0005359 A1, Publication Date 1 January 2015)
in view of:
PICKERING (US 2014/0378551 A1, Publication Date 25 December 2014).
Teachings of BYMASTER are described above.
BYMASTER teaches that the compounds therein may be administered along with other therapeutic agents, such as opioids or N-methyl-D-aspartate receptor (NMDA) antagonists (paragraph [0253]).
BYMASTER does not teach specific time periods wherein amitifadine is administered before surgery. BYMASTER also does not provide any teachings related to patients with cognitive impairment.
Regarding claims 2-4 and 17: Claim 1 of PICKERING teaches the daily administration of memantine to a human patient who will undergo a surgical operation to prevent and treat post-operative pain. Claim 3 of PICKERING teaches administration from 1 to 28 days before the surgery. Claim 7 of PICKERING teaches administration for 1-16 days following the surgery. PICKERING teaches that administration of the memantine compositions therein causes NMDA receptors to be deactivated (paragraphs [0060] and [0020]).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to combine the method of administering memantine taught by PICKERING, including the pre-operative administration taught therein, with the method of administration of amitifadine for the treatment of pain taught by BYMASTER, for the purpose of producing an improved anti-pain effect in the patient and arriving at a specific pre-operative and post-operative administration schedule. One of ordinary skill in the art would have expected success in this combination, because both BYMASTER and PICKERING teach methods of treating pain, and because BYMASTER states that it may be useful to add an NMDA antagonist to the method of administration therein. “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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
The time period for pre-operative administration of the analgesic composition, taught by PICKERING, is 1-28 days and fully encompasses the instantly claimed ranges of 1-3 weeks, 2 weeks, or about 2 weeks up to a day prior to surgery. The post-operative administration time period, taught by BYMASTER, is less than or equal to 13 weeks and fully encompasses the instantly claimed periods of about 4 weeks, about 12 weeks, or about a day after surgery onward. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). See MPEP 2144.05(I).
Regarding claim 23: PICKERING teaches that memantine is known to be useful for the treatment Alzheimer’s disease (paragraph [0007]). It would have been obvious to one of ordinary skill in the art that the combined administration of memantine and amitifadine, rendered obvious by BYMASTER and PICKERING, would be useful to treat pain in a population with Alzheimer’s disease, wherein patients often exhibit cognitive impairment.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN D MCANANY whose telephone number is (571)270-0850. The examiner can normally be reached 8:30 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ANDREW D KOSAR can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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