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 34-43 have been added.
Claims 1-7, 10, 14-16, 25-43 are pending.
Claims 1-7, 10, 14-16, 25-43 are rejected.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 9 August 2023; 15 May 2024; 24 July 2025; and 17 February 2026 have been acknowledged and considered.
Claim Interpretation
Claim 1 recites the word “preventing” and claim 34 recites the word “reversing.” These words are not defined in the instant specification and are therefore given their broadest reasonable interpretation. According to Taber’s Medical Dictionary, “prevention” is defined as “the anticipation of harm, disease, or injury and the measures taken to block their effects” (p. 1945). The word “reversing” is not present but the related word “reversion” is defined as “a return to a former condition, as from illness to health.” (p. 2087). Claims 1 and 34 have been interpreted as the definitions taken from Taber’s Medical Dictionary.
Claim Rejections - 35 USC § 112(a) - Scope of Enablement
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.
Claims 1-7, 10, 14-16, and 25-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. Claims 1-7, 10, 14-16, 25-33 contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification, while being enabled for treating and preventing certain types of neuropathic pain with and without comorbid cognitive deficits, does not reasonably provide enablement for a method of preventing all types of neuropathic pain with and without comorbid cognitive deficits.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
(A) The breadth of the claims are broad in scope. The claims recite: “A method of treating, inhibiting, or preventing [cognitive deficit comorbid with] neuropathic pain…” This method of preventing extends to all types of neuropathic pain with a vast population of subjects. Thus, the claims are broad in that they cover prevention of all types of neuropathic pain by administering eFT508. The specification discloses: “There are many different causes of neuropathic pain, including trauma to peripheral nerves, metabolic disease, and toxicities produced by drug treatment, all of which are growing indications.” (Spec., p. 1). The claim therefore encompasses a method of preventing all types of neuropathic pain by administering eFT508.
(B) The nature of the invention generally relates to the pharmaceutical art and more specifically to a method for treating, inhibiting, or preventing neuropathic pain, with or without comorbid deficits, comprising administering an effective amount of eFT508 sufficient to treat, inhibit, prevent said neuropathic pain with or without comorbid deficits. The instant specification states: “The economic impact of pain is equally large at approximately $100 billion annually. Opioid/narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their
clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. This complex pathophysiological cycle represents a critical barrier to the quality of life of these patients due to the resulting drug induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side-effects. Accordingly, there is major interest in new approaches to treat chronic pain without engendering tolerance or unacceptable side-effects.” (Spec. p.1). Thus, the nature of the invention is sophisticated.
(C) The state of the prior art is discussed in a review article which discusses, “…the necessity to assess drug efficacy in CIPNP independently of other neuropathic pain states, and emphasize[s] the need for delineation of subpopulations of patients with CIPNP for more-efficient treatment.” (Sisignano et al., p. 694). “The heterogeneity of main mechanisms in CIPNP is most probably the reason why trial results from classic neuropathic pain states, such as postherpetic neuralgia and painful diabetic neuropathy, do not successfully translate to treatment of CIPNP.” (Id., p. 704). Another review article states: “Primary prevention strategies (in generally healthy but at-risk individuals) include the live attenuated and subunit adjuvanted herpes zoster vaccines, which both reduce the likelihood of developing herpes zoster infections in individuals ≥50 years of age, and therefore, reduce the likelihood of postherpetic neuralgia.” (Colloca et al., p. 8). In view of the review articles, the state of the prior art demonstrates that a therapeutic designed for prevention of neuropathic pain is not agnostic to the type of neuropathic pain. Examiner is unaware of evidence from the prior that supports a claim for eFT508 preventing all types of neuropathic pain, like postherpetic neuralgia.
(D) The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Ent. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
(E) The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brane, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
(F) The amount of direction provided by the inventor includes background information about neuropathic pain: “Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes (see diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery. After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli.” (Spec., p.19). The specification does not provide detailed guidance regarding the use of eFT508 to prevent neuropathic pain in indications like diabetic neuropathy, multiple sclerosis, herpes zoster infection, etc.
(G) The existence of working examples relates to methods of preventing CIPN induced by paclitaxel. More specifically, paclitaxel-treated mice given eFT508 (10 mg/kg) after full development of CIPN showed a reversal of mechanical and thermal hypersensitivity, which was further corroborated by testing the specificity of eFT508 with dosing to WT mice and mice with a point mutation S209A to preclude endogenous phosphorylation of eIF4E (FIGS. 8B-8D; page 43, lines 10-17). SNI animals treated with tomivosertib showed no cognitive impairment on rule-shifting day when compared to SNI + vehicle animals (Fig. 13A; p. 68, lines 1-5). There are no examples for a method of preventing all types of neuropathic pain, only chemotherapy induced peripheral neuropathy (CIPN) induced by paclitaxel and peripheral nerve injury induced by spared nerve injury (SNI). The amount of direction or guidance is minimal or non-existent with regards to preventing other types of neuropathic pain, like those resulting from diabetes, multiple sclerosis, arthritis, an autoimmune disease, or an infection (Spec, p. 3, lines 21-25) by administering eFT508, just pain related to peripheral nerve injury and CIPN.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. Without any direction as to how to administer eFT508 to prevent all types of neuropathic pain, a burdensome amount of research would be required by one of ordinary skill in the art to bridge this gap. The guidance and direction provided by the instant disclosure for "preventing” all types of neuropathic pain is not sufficient to enable a skilled artisan to practice the invention commensurate with the full scope of the claims without undue experimentation for the following reasons: the breadth of the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art demonstrates that a therapeutic designed for prevention of neuropathic pain is not agnostic to the type of neuropathic pain; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to preventing neuropathic pain through induction of CIPN by paclitaxel and peripheral nerve injury by SNI; does not demonstrate possession of a method of preventing all types of neuropathic pain within the scope of, “A method of treating, inhibiting, or preventing [cognitive deficit comorbid with] neuropathic pain …”; and the quantity of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends amending the claims to omit the term “preventing” or include a limitation in the claim that explicitly includes prevention limited to CIPN induced by paclitaxel or peripheral nerve injury by SNI.
Claims 34-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. Claims 34-43 contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification, while being enabled for reversing neuropathic pain in models of CIPN induced by paclitaxel, does not reasonably provide enablement for a method of reversing all types of neuropathic pain.
The Wands factors are analyzed with respect to the claimed invention in turn below.
(A) The breadth of the claims is broad in scope. The claim recites: “A method of reversing neuropathic pain…” This method extends to reversing all types of neuropathic pain with a vast population of subjects. The specification discloses: “There are many different causes of neuropathic pain, including trauma to peripheral nerves, metabolic disease, and toxicities produced by drug treatment, all of which are growing indications.” (Spec., p. 1). The claim therefore encompasses a method of reversing all types of neuropathic pain by administering eFT508.
(B) The nature of the invention generally relates to the pharmaceutical art and more specifically to a method of reversing neuropathic pain comprising administering an effective amount of eFT508 sufficient to reverse said neuropathic pain. The instant specification states: “The economic impact of pain is equally large at approximately $100 billion annually. Opioid/narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. This complex pathophysiological cycle represents a critical barrier to the quality of life of these patients due to the resulting drug induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side-effects. Accordingly, there is major interest in new approaches to treat chronic pain without engendering tolerance or unacceptable side-effects.” (Spec. p.1). Thus, the nature of the invention is sophisticated.
(C) The state of the prior art is discussed in a review article which states, “…the late phases of diabetic neuropathy are poorly reversible or even irreversible.” (Boucek et al., p.143). Furthermore, “In spite of the plethora of pathogenetic concepts based on extensive experimental research there is still a lack of effective measures derived from successful clinical trials to reverse the course of established diabetic neuropathy.” (Id., p.150). Another review article states, “…the necessity to assess drug efficacy in CIPNP independently of other neuropathic pain states, and emphasize[s] the need for delineation of subpopulations of patients with CIPNP for more-efficient treatment.” (Sisignano et al., p. 694). “The heterogeneity of main mechanisms in CIPNP is most probably the reason why trial results from classic neuropathic pain states, such as postherpetic neuralgia and painful diabetic neuropathy, do not successfully translate to treatment of CIPNP.” (Id., p. 704). In view of the review articles, the state of the prior art demonstrates that late phases of diabetic neuropathy are poorly reversible or even irreversible and that efficacy of drugs to treat CIPN needs to be independently assessed from other neuropathic pain states. Examiner is unaware of evidence from the prior that supports a claim for eFT508 reversing all types of neuropathic pain, like diabetic neuropathy.
(D) The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Ent. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
(E) The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brane, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
(F) The amount of direction provided by the inventor includes background information about neuropathic pain: “Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes (see diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery. After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli.” (Spec., p.19). The specification does not provide detailed guidance regarding the use of eFT508 to reverse neuropathic pain in indications like diabetic neuropathy, multiple sclerosis, herpes zoster infection, etc.
(G) The existence of working examples relates to methods of reversing neuropathic pain. More specifically, paclitaxel-treated mice given eFT508 (10 mg/kg) after full development of CIPN showed a reversal of mechanical and thermal hypersensitivity, which was further corroborated by testing the specificity of eFT508 with dosing to WT and mice with a point mutation S209A to preclude endogenous phosphorylation of eIF4E (FIGS. 8B-8D; page 43, lines 10-17). SNI animals treated with tomivosertib showed no cognitive impairment on rule-shifting day when compared to SNI + vehicle animals (Fig. 13A; p. 68, lines 1-5). However, the instant specification states, “Despite the profound effect on PNI-induced rule-shifting deficits, tomivosertib-treatment had no effect on mechanical withdrawal thresholds when assessed 1 or 3 hours after treatment on days 1 and 5 of the 7-day treatment schedule (FIG. 13C).” The disclosure acknowledges the reversal of neuropathic seen with CIPN induced by paclitaxel was not seen to the same extent with peripheral nerve injury induced by SNI. There are no examples for a method of reversing all types of neuropathic pain, only CIPN induced by paclitaxel. Thus, the amount of direction or guidance is minimal or non-existent with regards to reversing all types of neuropathic pain by administering eFT508, only neuropathic pain through paclitaxel induced CIPN.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. Without any direction as to how to administer eFT508 to reverse all types of neuropathic pain, a burdensome amount of research would be required by one of ordinary skill in the art to bridge this gap. The guidance and direction provided by the instant disclosure for "reversing” all types of neuropathic pain is not sufficient to enable a skilled artisan to practice the invention commensurate with the full scope of the claims without undue experimentation for the following reasons: the breadth of the claims is broad in scope; the nature of the invention is sophisticated; the prior art demonstrates that neuropathic pain resulting from late phase diabetic neuropathy is poorly reversible or irreversible and that efficacy of drugs to treat CIPN needs to be independently assessed from other neuropathic pain states; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to reversing neuropathic pain through induction of CIPN by paclitaxel; does not demonstrate possession of a method of preventing all types of neuropathic pain within the scope of, “A method of reversing neuropathic pain…”; and the quantity of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends amending the claims to omit the term “reversing” or include a limitation in the claim that explicitly includes reversal of CIPN induced by paclitaxel.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 3-7, 10, 14-16, and 34-43 are rejected under 35 U.S.C. 103 as being unpatentable over Reich 2015 (A1 in IDS submitted 8/9/2023) in view of Moy et al. (C17 in IDS submitted on 8/9/2023), Jay et al. (C11 in IDS submitted 8/9/23), and Gopal et al. (Ajay K. Gopal, et al. A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies, Blood, Vol. 130, No. 1, p. 4624, 2017).
Reich 2015 teaches administration of MNK inhibitors [0001] for e.g. relieving pain [0170].
Claim 15 displays the structure of eFT508 as a preferred embodiment of the disclosed MNK inhibitors (p. 382, column 3 row 4).
Claim 18 states, “Use of (i) a compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition of claim 17, in the manufacture of a medicament for treating a MNK dependent condition in a mammal in need thereof.”
[0148] defines a “mammal” to include, “humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits)….”
[0784] states, “Compounds in accordance with the present invention are candidate therapeutics for treating MNK related disorders, such as inflammatory disorders and cancer.”
[0166] states, “…the disclosed compounds are useful for inhibiting the activity of MNK for preventing, treating, or ameliorating a symptom associated with a disease, disorder, or pathological condition involving MNK…A compound which inhibits the activity of MNK will be useful in preventing…the symptoms or progression of diseases of…inappropriate cellular inflammatory responses… particularly in which the inappropriate cellular inflammatory responses is mediated by MNK…”
[0167] states, “… the inventive compounds…are candidate therapeutics for the prophylaxis and/or therapy or cytokine related diseases, such as inflammatory diseases… Exemplary inflammatory diseases include without limitation, chronic or acute inflammation…”
[0181] states, “Therapeutically effective dosages of a compound according to Formula I or a composition of a Formula I compound will generally range … from about 10 to about 50 mg/day. The therapeutically effective dosages may be administered (typical routes of administering are defined in [0149], which includes infusion techniques) in one or multiple doses.”
Reich 2015 discloses eFT508, a method of administering eFT508 to a mammal facing a MNK dependent condition in need of treatment including both humans and animals, and a method wherein eFT508 is administered with an additional agent as a combination therapy at distinct times ([0178]).
Reich 2015 does not teach administration of eFT508 for the treatment of neuropathic pain.
Moy et al. teaches inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activate protein kinase (MAPK) pathways, which block the development of nociceptor sensitization. Phosphorylation of the eukaryotic translation initiation factor (eIF) 4E by its specific MAPK interacting kinases (MNK)1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Factors contributing to mechanical and thermal hypersensitivity, affective pain behaviors, and hyperalgesic priming is reduced in mice lacking eIF4E phosphorylation (eIF4ES209A). Mice induced with the eIF4ES209A point mutation, knockout of the Mnk1/2-/- genes, and inhibition of MNK1/2 by cercosporamide, lead to attenuation of nerve growth factor (NGF) and interleukin-6 (IL6) (p. 7481, Abstract).
Moy et al. teaches NGF induced changes in dorsal root ganglia (DRG) excitability in the presence of cercosporamide (10 µM) inhibited NGF induced hyperexcitability demonstrating that brief pharmacological inhibition of MNK1/2 reverses augmented excitability in DRG neurons induced by NGF treatment (p. 7489).
Figure 1E shows decreased mechanical hypersensitivity in acute pain with mice possessing the eIF4ES209A point mutation (pp. 7484-7485).
Figure 12E shows decreased neuropathic pain through MNK1/2 inhibition via cercosporamide (p. 7495).
Moy et al. teaches that genetic and pharmacological experiments demonstrate MNK1/2 may be advantageously targeted for treatment and/or prevention of chronic pain conditions (p. 7495).
Moy et al. teaches administering an MNK1/2 inhibitor, cercosporamide, for the treatment of acute and chronic neuropathic pain.
Moy et al. does not teach treating neuropathic pain using a secondary agent like opioids or gabapentenoid.
Jay et al. teaches “Viral, bacterial, aseptic inflammation…have all been implicated in the production of pain.” Chemotherapy treatment is a common cause of neuropathic pain as shown in Table 1 (p.7).
Jay et al. also describes utilization of anti-pain agents, including opioids and gabapentin for treating neuropathic pain, whether as a monotherapy or adjuvant therapy (p. 21, bottom paragraph; p.29, 5th paragraph; p.37, 2nd paragraph).
Jay et al. does not teach a method wherein eFT508 is delivered over a period of one week to three years for the treatment of cancer.
Gopal et al. teaches a method of utilizing eFT508 for the treatment of hematological malignancies in which eFT508 is delivered once daily at a starting dose of 300 mg where efficacy evaluations were performed every 6 weeks (methods, p.2).
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention, to modify the teachings of Reich 2015, to incorporate the teachings of Moy et al., Jay et al., and Gopal et al., and thereby arrive at the method instantly claimed. A skilled artisan would have been motivated to arrive at the claimed invention through the combined teachings because, Reich 2015 teaches a method of treating mammals by administering eFT508, an MNK inhibitor, to treat, inhibit, or prevent MNK related conditions, disorders, diseases, etc.; Moy et al. teaches a method of preventing and reversing neuropathic pain by inhibiting MNK1/2 via cercosporamide treatment; Jay et al. teaches administration of chemotherapy is a common cause of neuropathic pain and also teaches the utilization of anti-pain agents, including opioids and gabapentin for treating neuropathic pain; and Gopal et al. teaches a method of utilizing eFT508 for the treatment of hematological malignancies in a time interval of 6 weeks. It would have been prima facie obvious to a PHOSITA to substitute cercosparimde for eFT508 because Reich 2015 teaches relatively few inhibitors have been made with regard to MNK inhibitors: including CGP052088, CGP57380, and cercosporamide ([0008]). Substituting cercosporamide for eFT508 would have been prima facie obvious to a PHOSITA because Reich 2015 teaches cercosporamide is an equivalent MNK inhibitor in the art. Therefore, substituting the known MNK inhibitor cercosporamide taught by Moy et al., for the MNK inhibitor eFT508 taught by Reich 2015, to prevent and reverse neuropathic pain in a subject by administering a sufficient amount of eFT508, would have been prima facie obvious (MPEP §2144.06(II)). Accordingly, claims 1, 3-4, 7, 10, 14, and 34-36, 39-41 are not patentable over the cited references.
Regarding claims 5-6 and 37-38, Moy et al. teaches the point mutation eIF4ES209A and treatment with cercosporamide of mice exhibiting neuropathic pain are effective in treating acute and chronic pain, respectively (vide supra). “… targeting MNK1/2 recapitulates the phenotype of eIF4E209A mice…” (p. 7495, Discussion). Therefore, it would have been prima facie obvious to substitute cercosporamide for eFT508 to prevent acute and chronic neuropathic pain. A PHOSITA would have had a reasonable expectation of success treating acute neuropathic pain by inhibiting MNK1/2 as it is taught to recapitulate the phenotype of the point mutation.
Regarding claims 15-16 and 42-43, Gopal et al., teaches a method of treating patients exhibiting hematological malignancies with eFT508 once daily for 6-week intervals, and analysis was done on the 6-week and 12-week (four month) time points. Reich 2015 teaches different routes of typical administration, like infusion techniques (vide supra). It would have been prima facie obvious to a PHOSITA to dose a patient via continuous infusion taught by Reich 2015 through routine optimization, and at the time intervals taught by Gopal et al., which overlap with the instant claims (MPEP §2144.05(I)(II)).
Claims 2 and 25-33 are rejected under 35 U.S.C. 103 as being unpatentable over Reich 2015 (A1 in IDS submitted 8/9/2023) in view of Moy et al. (C17 in IDS submitted on 8/29/2023), Jay et al. (C11 in IDS submitted 8/9/23), and Gopal et al. (Ajay K. Gopal, et al. A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies, Blood, Vol. 130, No. 1, p. 4624, 2017), further in view of Leite-Almeida et al. (The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats, PAIN, Vol. 144, No. 1-2, pp. 57-65, 2009).
The teachings of Reich 2015, Moy et al., Jay et al., and Gopal et al., are discussed above, but do not teach a method of treating a cognitive deficit comorbid with neuropathic pain.
This deficit is remedied by Leite-Almeida et al. which teaches the influence of neuropathic pain on affective and cognitive behaviors and how locomotor and exploratory activities decreased steadily with age and were further potentiated by spared nerve injury (SNI) (Abstract). Leite-Almeida et al. teaches “…the influence of neuropathic pain on affective and cognitive behaviors is age dependent and varies with the behavioral domain that is tested. Importantly, mid-aged animals seem to be more susceptible to depression and cognitive deterioration associated to chronic pain than young and old groups…” (Abstract). In the analysis provided, Leite-Almeida et al. teaches how neuropathic pain affects behavioral performance in both emotional and cognitive tasks further providing “…a plausible contribution for augmented anxiety levels, depressive symptoms and cognitive impairments in aged subjects” (page 1, paragraph 2).
It would have been prima facie obvious to a PHOSITA before the effective filing date, to modify the teachings of Reich 2015, Moy et al., Jay et al., and Gopal et al., by incorporating the teachings of Leite-Almeida et al. and thereby arrive at the method instantly claimed. A skilled artisan would have been motivated to arrive at the claimed invention because, Reich 2015 teaches a method of treating mammals by administering eFT508, an MNK inhibitor, alone or in combination with an additional agent to treat, inhibit, or prevent MNK related conditions, disorders, diseases, etc.; Moy et al. teaches a method of preventing and reversing neuropathic pain by inhibiting MNK1/2 via cercosporamide treatment; Jay et al. teaches administration of chemotherapy is a common cause of neuropathic pain and also the utilization of anti-pain agents, including opioids and gabapentin for treating neuropathic pain; and Gopal et al. teaches a method of utilizing eFT508 for the treatment of hematological malignancies in a time interval of 6 weeks. A skilled artisan would have been motivated to combine the teachings of the above references with the teachings of Leite-Almeida et al., because Leite-Almeida et al. teaches neuropathic pain is comorbid with cognitive deficits (vide supra). The comorbidities associated with neuropathic pain are inherent in the teachings of Leite-Almeida et al. (MPEP §§2112(II)). Therefore, a skilled artisan would have had a reasonable expectation of success because eFT508 serves as a treatment of neuropathic pain, an MNK related disorder, and therefore would treat the underlying condition potentiating the cognitive comorbid deficiencies, like emotional and cognitive tasks. Accordingly, claims 2 and 25-33 are not patentable over the cited references.
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, 7, 10, 14-16, 25, 29-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,925,642 (‘642) in view of Biondi et al. (Is migraine a neuropathic pain syndrome?, Current Science Inc, 10, 167–178 (2006)).
Although the claims at issue are not identical, they are not patentably distinct from each other because ‘642 claims a method of administrating eFT508 in order to prevent, treat, or inhibit migraine in a human subject.
Claims 1-19 of ‘642 recite a method of preventing, treating, or inhibiting migraine in a human subject with a first therapeutic selected from cercosporamide, eFT508, or 4EF-1 and a second therapeutic selected from the aforementioned therapeutics, a non-narcotic analgesic, and opiate analgesic, etc. sufficient to prevent, treat, or inhibit said migraine by suppressing or inhibiting translation, suppressing or inhibiting eIF4E, and/or suppressing or inhibiting phosphorylation of 4E-BP or Ser209 of eIF4E in a subject.
‘642 does not teach a method of treating subjects possessing neuropathic pain, with or without comorbid cognitive deficits, by administering only eFT508 or in combination with an opiate analgesic.
Biondi et al. teaches that clinical features of migraines are evocative of those traditionally associated with neuropathic pain (Abstract, lines 9-11). Biondi also teaches “Based on a synthesis of clinical and preclinical evidence that is currently available, migraine is an episodic or chronic pain disorder that is the result of both peripheral neurogenic inflammation resulting in nociceptive pain and, in most cases, central sensitization resulting in clinical symptoms that are typical of neuropathic pain disorders.” Furthermore, inflammatory nociceptive pain is effectively relieved by acetaminophen, NSAIDs, or opioid analgesics (page 173, col., 2, paragraph 3).
It would have been prima facie obvious to a PHOSITA to modify the teachings of ‘642 to incorporate the teachings of Biondi et al. to treat neuropathic pain with eFT508 because Biondi et al. teaches the clinical features of migraines are evocative of those traditionally associated with neuropathic pain. A PHOSITA would have had a reasonable expectation of success in treating neuropathic pain because Biondi et al. further teaches that “Scientific evidence suggests that the initial pain of a migraine attack is caused by trigeminal nociceptor activation as a consequence of neurovascular inflammation in the meninges and around cranial blood vessels.” (Id.). A PHOSITA would have recognized through the teachings of Biondi et al. that the underlying conditions of a migraine are typical of neuropathic pain disorders and would have repurposed eFT508 to treat neuropathic pain (MPEP §2112 (I)-(III)).
Claims 34-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,925,642 (‘642) in view of further in view of Moy et al., (C17 in IDS submitted on 8/9/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because ‘642 claims a method of administrating eFT508 in order to prevent, treat, or inhibit migraine in a human subject.
The teachings of the claims of ‘642 are discussed above, but do not teach reversing neuropathic pain.
Moy et al. teaches inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activate protein kinase (MAPK) pathways block the development of nociceptor sensitization. Phosphorylation of the eukaryotic translation initiation factor (eIF) 4E by its specific MAPK interacting kinases (MNK) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Factors contributing to mechanical and thermal hypersensitivity, affective pain behaviors, and hyperalgesic priming is reduced in mice lacking eIF4E phosphorylation (eIF4ES209A). Mice induced with the eIF4ES209A point mutation, knockout of the Mnk1/2-/- genes, and inhibition of MNK1/2 by cercosporamide, lead to attenuation of nerve growth factor (NGF) and interleukin-6 (IL6). NGF induced changes in dorsal root ganglia (DRG) excitability in the presence of cercosporamide (10 µM) inhibited NGF induced hyperexcitability demonstrating that brief pharmacological inhibition of MNK1/2 reverses augmented excitability in DRG neurons induced by NGF treatment (p. 7489). Furthermore, Figure 12E shows decreased neuropathic pain through MNK1/2 inhibition via cercosporamide (p. 7499).
It would have been prima facie obvious to a PHOSITA to modify the teachings of ‘642 to incorporate the teachings of Moy et al. to reverse neuropathic pain with eFT508 because Moy et al. teaches a method of reversing neuropathic pain by inhibiting MNK1/2 via cercosporamide treatment. A PHOSITA would have had a reasonable expectation of success in treating neuropathic pain with eFT508 because Moy et al. teaches factors contributing to mechanical and thermal hypersensitivity, affective pain behaviors, and hyperalgesic priming is reduced in mice lacking eIF4E phosphorylation and the same results were seen with treatment of mice with cercosporamide (Id.). A PHOSITA would have recognized that cercosporamide reverses neuropathic pain though the teachings of Moy et al. and that cercsporamide and eFT508 are art recognized equivalents through the teachings of ‘642 and would have simply substituted cercosporamide for eFT508 (MPEP §2144.06(II)).
Response to Arguments
Applicant's arguments filed on 7/24/2025 have been fully considered and are persuasive with respect to arguments made for rejections under 35 U.S.C. 103 and 35 U.S.C. 112(a). The non-final rejection filed on 1/27/2025 has been withdrawn with respect to the previous rejections made under 35 U.S.C. 103 and 35 U.S.C 112(a).
Applicant’s arguments filed on 7/24/2025 are not persuasive with respect to arguments made for rejections under Obviousness-type Double Patenting.
With respect to the obviousness-type double patenting rejection of claims 1-3, 7, 10, 14-16, 25, and 29-33, applicant asserts that Biondi et al. only presents a hypothesis that migraines may be related to neuropathic pain, because Biondi et al. states “…it is certain that debate over this issue will continue.” Further asserted, is that Biondi et al. is a speculative disclosure and would not have prompted a PHOSITA to treat neuropathic pain through the combined teachings of ’642 and Biondi et al. However, Biondi et al. also states “Based on a synthesis of clinical and preclinical evidence that is currently available, migraine is an episodic or chronic pain disorder that is the result of both peripheral neurogenic inflammation resulting in nociceptive pain and, in most cases, central sensitization resulting in clinical symptoms that are typical of neuropathic pain disorders.” (vide supra).
MPEP §2141.02(VI) states “A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984) (Claims were directed to a process of producing a porous article by expanding shaped, unsintered, highly crystalline poly(tetrafluoroethylene) (PTFE) by stretching said PTFE at a 10% per second rate to more than five times the original length. The prior art teachings with regard to unsintered PTFE indicated the material does not respond to conventional plastics processing, and the material should be stretched slowly. A reference teaching rapid stretching of conventional plastic polypropylene with reduced crystallinity combined with a reference teaching stretching unsintered PTFE would not suggest rapid stretching of highly crystalline PTFE, in light of the disclosures in the art that teach away from the invention, i.e., that the conventional polypropylene should have reduced crystallinity before stretching, and that PTFE should be stretched slowly). Allied Erecting v. Genesis Attachments, 825 F.3d 1373, 1381, 119 USPQ2d 1132, 1138 (Fed. Cir. 2016) ("Although modification of the movable blades may impede the quick change functionality disclosed by Caterpillar, ‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine.’"(quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed Cir. 2006) (citation omitted))). However, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”
Biondi et al. must be considered as a whole. Applicants’ assertion, that Biondi et al. discloses there is an ongoing debate regarding the link between neuropathic pain and migraines, does not obviate the fact, that there is substantial preclinical and clinical evidence supporting that migraines are a result of both peripheral neurogenic inflammation and, in most cases, central sensitization resulting in clinical symptoms that are typical of neuropathic pain disorders (vide supra).
Therefore, the obviousness-type double patenting rejection of claims 1-3, 7, 10, 14-16, 25, and 29-33 is maintained.
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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