DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08 June 2026 has been entered.
Status of Claims
Receipt is acknowledged of the claim amendments filed on 08 June 2026.
Claims 1-62 and 75 are cancelled.
Claims 63-64, 66-74, 76-77 and 79-87 have been amended.
Claims 88-89 have been added.
Claims 63-74 and 76-89 are presented for examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) filed 06/09/2026 has been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Claim Objections
Claims 63-74 and 76-87 are objected to because the claims do not refer back to a preceding claim (e.g., depends directly or indirectly on claims 88 or 89, respectively). “One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application. Any dependent claim which refers to more than one other claim ("multiple dependent claim") shall refer to such other claims in the alternative only. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. For fee calculation purposes under § 1.16, a multiple dependent claim will be considered to be that number of claims to which direct reference is made therein. For fee calculation purposes also, any claim depending from a multiple dependent claim will be considered to be that number of claims to which direct reference is made in that multiple dependent claim. In addition to the other filing fees, any original application which is filed with, or is amended to include, multiple dependent claims must have paid therein the fee set forth in § 1.16(j). Claims in dependent form shall be construed to include all the limitations of the claim incorporated by reference into the dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of each of the particular claims in relation to which it is being considered.” See MPEP 608.01(i) and 608.01(n)(I)(B)(2). Appropriate correction is required.
Rejections Maintained and Modified as Necessitated by the Claim Amendments
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 63-74 and 88 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over SHIMIZU (“Intrathecal lithium reduces neuropathic pain responses in a rat model of peripheral neuropathy”, Pain 85, pages 59-64, 2000; cited in IDS filed 02/17/2023) in view of JOHNSON (US 2006/0160843 A1, cited in IDS filed 12/02/2022 (9 pages), publication date of 20 July 2006) and WATTS (WO 2010/048446 A2, publication date of 29 April 2010).
Shimizu is primarily directed towards intrathecal Li+ suppressing neuropathic pain response in a rate model of peripheral neuropathy (abstract).
Regarding claims 66, 69 and 72 and 88, Shimizu discloses that intracellular phosphatidylinositol (PI) second messenger system has a critical role in the development of neuropathic pain (page 59, first column, first paragraph). Shimizu discloses that Li+ indirectly inhibits the intracellular PI second messenger system in hyperactivated CNS neurons, thus suppresses neuropathic pain response (page 63, second column, first paragraph). Shimizu discloses that intrathecal administration of Li+ reduces heat hyperalgesia, cold allodynia and mechanical allodynia (e.g., reduces likelihood of peripheral neuropathy) (page 63, first column, third paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph).
Regarding claim 64, Shimizu discloses administration of lithium chloride to provide the Li+ (page 61, first column, second paragraph).
Shimizu does not specifically teach treating peripheral neuropathy in a subject undergoing anticancer treatment with paclitaxel; and co-administering lithium to the subject treated with paclitaxel. The deficiencies are made up for by the teachings of Johnson and Watts.
Johnson is primarily directed towards use of ibudilast for treating neuropathic pain (abstract).
Regarding claims 63 and 88, Johnson discloses neuropathic pain can occur from chemical injury including chemotherapeutics (paragraph [0013]). Johnson discloses that chemotherapeutic agents known to result in patient neuropathy include taxol (paragraph [0073]). Johnson teaches a test where neuropathic pain was induced by administration of a taxol, specifically paclitaxel (e.g., only taxane anticancer treatment being administered) (paragraph [0177]).
Watts is primarily directed treatment of neurological disorders and nervous system injuries (abstract).
Regarding claims 63 and 88, Watts teaches methods for inhibiting degeneration of a neuron or a portion thereof comprising administering an agent that modulates the activity or expression of a target protein in the neuron or portion thereof (page 1, third paragraph). Watts teaches that the agent including lithium chloride (page 2, third paragraph; page 6, first paragraph). Watts teaches that the subject have or is at risk of developing including disorder of the nervous system (page 2, last paragraph). Watts teaches that disorders of the nervous system including peripheral neuropathies (page 3, first paragraph). Watts teaches administration of a combination of paclitaxel with an agent to protect against peripheral neuropathy (e.g., only taxane anticancer treatment being administered) (page 91, second paragraph).
Regarding claim 65, Shimizu discloses administration of lithium chloride to provide the Li+ (page 61, first column, second paragraph).
Regarding claims 67-68, 70-71 and 73-74, Shimizu discloses that Li+ indirectly inhibits the intracellular PI second messenger system in hyperactivated CNS neurons, thus suppresses neuropathic pain response (page 63, second column, first paragraph). Shimizu discloses that intrathecal administration of Li+ reduces heat hyperalgesia, cold allodynia and mechanical allodynia (e.g., reduces likelihood of peripheral neuropathy) (page 63, first column, third paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph).It would have been prima facie obvious to the person of ordinary skill in the art at the time the invention was made to suppress neuropathic pain response (e.g., inhibiting peripheral neuropathy) or reduce neuropathic pain in a subject with cancer by administering an anti-cancer agent including paclitaxel and an effective amount of lithium chloride to treat neuropathic pain. The person of ordinary skill in the art would have been motivated to make those modifications to suppress neuropathic pain response (e.g., inhibiting peripheral neuropathy) or reduce neuropathic pain (e.g., peripheral neuropathy) in subjects including subjects that have neuropathic pain due to chemotherapeutic agents including paclitaxel which Johnson teaches and administered the composition which is able to treat neuropathic pain in combination with the chemotherapeutic agents in order to provide suppression or reduction of the neuropathic pain (e.g., peripheral neuropathy) which is taught by Watts, and reasonably would have expected success because Johnson discloses neuropathic pain can occur from chemical injury including chemotherapeutics (paragraph [0013]). Johnson discloses that chemotherapeutic agents known to result in patient neuropathy include taxol (paragraph [0073]). Johnson teaches a test where neuropathic pain was induced by administration of a taxol, specifically paclitaxel (e.g., only taxane anticancer treatment being administered) (paragraph [0177]). Watts teaches that disorders of the nervous system including peripheral neuropathies (page 3, first paragraph). Watts teaches administration of a combination of paclitaxel with an agent to protect against peripheral neuropathy (e.g., only taxane anticancer treatment being administered) (page 91, second paragraph).
Claims 76-87 and 89 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over SHIMIZU (“Intrathecal lithium reduces neuropathic pain responses in a rat model of peripheral neuropathy”, Pain 85, pages 59-64, 2000; cited in IDS filed 02/17/2023) in view of JOHNSON (US 2006/0160843 A1, cited in IDS filed 12/02/2022 (9 pages), publication date of 20 July 2006), MEKHAIL (“Paclitaxel in cancer therapy”, Expert Opinion on Pharmacotherapy, 3:6, 755-766, 2002), MCGOVERN (US 2010/0222287 A1, publication date of 02 September 2010) AND WATTS (WO 2010/048446 A2, publication date of 29 April 2010).
Shimizu is primarily directed towards intrathecal Li+ suppressing neuropathic pain response (abstract).
Regarding claims 79-87 and 89, Shimizu discloses that intracellular phosphatidylinositol (PI) second messenger system has a critical role in the development of neuropathic pain (page 59, first column, first paragraph). Shimizu discloses that Li+ indirectly inhibits the intracellular PI second messenger system in hyperactivated CNS neurons, thus suppresses neuropathic pain response (page 63, second column, first paragraph). Shimizu discloses that intrathecal administration of Li+ reduces heat hyperalgesia, cold allodynia and mechanical allodynia (e.g., reduces likelihood of peripheral neuropathy) (page 63, first column, third paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph).
Regarding claim 77, Shimizu discloses administration of lithium chloride to provide the Li+ (page 61, first column, second paragraph).
Shimizu does not specifically teach treating peripheral neuropathy in a subject who is suffering lung cancer, breast cancer, ovarian cancer, or prostate cancer; and co-administering lithium to the subject treated with paclitaxel. The deficiencies are made up for by the teachings of Johnson, Mekhail, McGovern and Watts.
Johnson is primarily directed towards use of ibudilast for treating neuropathic pain (abstract).
Regarding claim 89, Johnson discloses neuropathic pain can occur from chemical injury including chemotherapeutics (paragraph [0013]). Johnson discloses that chemotherapeutic agents known to result in patient neuropathy include taxol (paragraph [0073]). Johnson teaches a test where neuropathic pain was induced by administration of a taxol, specifically paclitaxel (paragraph [0177]).
Mekhail is primarily directed towards paclitaxel in cancer therapy (see entire non-patent literature).
Regarding claims 76 and 89, Mekhail teaches paclitaxel can be used to treat breast, ovarian and lung cancer (page 763, first column, first paragraph).
Regarding claims 78, 81-81, 83-84 and 86-87, Shimizu discloses that Li+ indirectly inhibits the intracellular PI second messenger system in hyperactivated CNS neurons, thus suppresses neuropathic pain response (page 63, second column, first paragraph). Shimizu discloses that intrathecal administration of Li+ reduces heat hyperalgesia, cold allodynia and mechanical allodynia (e.g., reduces likelihood of peripheral neuropathy) (page 63, first column, third paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph).
McGovern is primarily directed towards method for treating prostate cancer (abstract).
Regarding claim 89, McGovern teaches that chemotherapeutics for treatment of prostate cancer include paclitaxel (paragraph [0008]).
Watts is primarily directed treatment of neurological disorders and nervous system injuries (abstract).
Regarding claims 89, Watts teaches methods for inhibiting degeneration of a neuron or a portion thereof comprising administering an agent that modulates the activity or expression of a target protein in the neuron or portion thereof (page 1, third paragraph). Watts teaches that the agent including lithium chloride (page 2, third paragraph; page 6, first paragraph). Watts teaches that the subject have or is at risk of developing including disorder of the nervous system (page 2, last paragraph). Watts teaches that disorders of the nervous system including peripheral neuropathies (page 3, first paragraph). Watts teaches administration of a combination of paclitaxel with an agent to protect against peripheral neuropathy (page 91, second paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art at the time the invention was made to suppress neuropathic pain response (e.g., inhibiting peripheral neuropathy) or reduce neuropathic pain (peripheral neuropathy) in a subject with lung cancer, breast cancer, ovarian cancer or prostate cancer by administering an anti-cancer agent including paclitaxel and an effective amount of lithium chloride to suppress neuropathic pain response (e.g., inhibiting peripheral neuropathy) or reduce neuropathic pain (peripheral neuropathy). The person of ordinary skill in the art would have been motivated to make those modifications to suppress neuropathic pain response (e.g., inhibiting peripheral neuropathy) or reduce neuropathic pain (e.g., peripheral neuropathy) in subjects including subjects that have neuropathic pain due to chemotherapeutic agents including paclitaxel which Johnson teaches and administered the composition which is able to treat neuropathic pain in combination with the chemotherapeutic agents in order to provide suppression or reduction of the neuropathic pain (e.g., peripheral neuropathy) which is taught by Watts, and reasonably would have expected success because Johnson discloses neuropathic pain can occur from chemical injury including chemotherapeutics (paragraph [0013]). Johnson discloses that chemotherapeutic agents known to result in patient neuropathy include taxol (paragraph [0073]). Johnson teaches a test where neuropathic pain was induced by administration of a taxol, specifically paclitaxel (e.g., only taxane anticancer treatment being administered) (paragraph [0177]). Watts teaches that disorders of the nervous system including peripheral neuropathies (page 3, first paragraph). Watts teaches administration of a combination of paclitaxel with an agent to protect against peripheral neuropathy (e.g., only taxane anticancer treatment being administered) (page 91, second paragraph).
Response to Arguments
Applicant argues on pages 7-8 of the response filed 08 June 2026 that Shimizu does not teach induction of peripheral neuropathy by the administration of paclitaxel or by any means other than by surgical ligation, Shimizu does not teach paclitaxel, Shimizu does not teach lithium was a viable therapy for preventing peripheral neuropathy occurring. Applicant argues that Shimizu teaches lithium only partially impacted surgically induced heat hyperalgesia, cold allodynia and mechanical allodynia present in subjects as a consequence of sciatic nerve surgery. Applicant argues that Shimizu does not absolutely teach that lithium could be used to prevent peripheral neuropathy from occurring secondary to the administration of paclitaxel during cancer therapy. Applicant argues at the bottom of page 8 that Johnson indicates that paclitaxel can induce peripheral neuropathy and that ibudilast, which is a compound completely unrelated by way of chemical structure and mechanism to Li+, may be used to treat/prevent the peripheral neuropathy caused by paclitaxel administration. Applicant argues that Johnson is inapposite to the instant invention and does not cure the deficiencies of Shimizu relative to the instantly claimed method. Applicant argues that Johnson does not even mention lithium. Applicant argues on page 9 that Watts teaches a laundry list of disease states and/or conditions which are mediated through myriad protein targets which result in neuronal degeneration and a laundry list of compounds and macromolecules, where lithium chloride is mentioned but not in relation to paclitaxel or peripheral neuropathy. Applicant argues that Example 6 of Watts which teaches a combination of paclitaxel with erlitinib inhibit or protect against peripheral neuropathy induced by paclitaxel, does not provide the use of lithium to prevent peripheral neuropathy occurring secondary to paclitaxel administration and the treatment of cancer.
Applicant's arguments filed on 08 June 2026 have been fully considered but they are not persuasive. In response, Shimizu discloses that Li+ indirectly inhibits the intracellular PI second messenger system in hyperactivated CNS neurons, thus suppresses neuropathic pain response (page 63, second column, first paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph). Therefore, from the disclosure of Shimizu, one of ordinary skill in the art would reasonably expect that Li+ can be administered to treat neuropathic pain. Applicant is reminded that obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). See MPEP 2143.02(II). Johnson discloses neuropathic pain can occur from chemical injury including chemotherapeutics (paragraph [0013]). Johnson discloses that chemotherapeutic agents known to result in patient neuropathy include taxol (paragraph [0073]). Johnson teaches a test where neuropathic pain was induced by administration of a taxol, specifically paclitaxel (paragraph [0177]). Watts teaches methods for inhibiting degeneration of a neuron or a portion thereof comprising administering an agent that modulates the activity or expression of a target protein in the neuron or portion thereof (page 1, third paragraph). Watts teaches that the agent including lithium chloride (page 2, third paragraph; page 6, first paragraph). Watts teaches that the subject have or is at risk of developing including disorder of the nervous system (page 2, last paragraph). Watts teaches that disorders of the nervous system including peripheral neuropathies (page 3, first paragraph). Thus, from the disclosure of Shimizu and the teachings of Johnson and Watts, one of ordinary skill in the art would have at least been motivated to try coadministration of lithium with paclitaxel to treat the neuropathic pain induced by administration of paclitaxel, as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Applicant argues from the bottom of page 9 to 10 that medical convention associated with years of experience utilizing lithium as a therapy evidences that the skilled practitioner would consider lithium administration a considerable risk element in contemplation of practicing the instantly claimed method. Applicant argues that the skilled practitioner cannot know from the teachings of Shimizu, Johnson and Watt how the interaction of paclitaxel with lithium would impact the peripheral neuropathy which occurs secondary to paclitaxel administration. Applicant argues that one of ordinary skill in the art would assume that combining lithium which has been shown in the art to produce peripheral neuropathy at the therapeutic levels would potentially have a significant deleterious effect on the peripheral neuropathy which is caused by paclitaxel because the skilled practitioner would not know the impact of lithium administration on paclitaxel induced peripheral neuropathy. Applicant argues that the skilled practitioner could not assume lower doses of lithium would have an actual effect given that paclitaxel was not texted in combination with lithium and the conclusions drawn by Shimizu with respect to lithium alone are both circumspect and speculative. Applicant argues that if higher doses of lithium alone are contraindicated then lower doses of lithium in combination with paclitaxel would also be highly suspect because the combined lithium and paclitaxel could easily be seen as potentially having an adverse additive effect on causing peripheral neuropathy. Applicant points to references including Sheean, Prettyman, and Megarbane for evidence that the medical convention recognized that the deleterious effects of lithium administration on neurotoxicity and in particular, peripheral neuropathy can occur at therapeutic and even sub-therapeutic levels.
In response, the references Licht, Johnston, Keltner, Sheean, Prettyman and Megarbane which teaches about the risk of lithium towards peripheral neuropathy, Licht teaches that there no statistical significance was reached and it was based on long-term lithium treatment, Johnston teaches 1000 mg/day of lithium for several years may cause toxicity as evidenced by peripheral neuropathy, Keltner teaches lithium dosed at 2,100 mg/day to an individual that suffered severe neuropathy, Sheean teaches that lithium is potentially toxic, that there is a large variation among patients in relation to what constitutes a toxic serum lithium level, and that both acute and chronic toxicity can occur with therapeutic range serum lithium levels, Prettyman teaches a lower dose of 400 mg daily that had a serum lithium level 10 hours following the last dose of 0.18 mmol/l, and Megarbane teaches serum lithium concentration in the therapeutic range of 0.4-0.8 mmol/L (e.g., requiring a normal dose, not a low dose as taught by Shimizu, to obtain the therapeutic serum lithium concentration). While, Shimizu discloses lower doses of including 40, 20, 10, 5 and 2.5 µmol of lithium chloride (e.g., 40 µmol of lithium is about .2776 mg) (page 61, first column, second paragraph). Shimizu discloses that Li+ therapy might be useful in the management of human neuropathic pain (page 63, second column, third paragraph). Therefore, one of ordinary skill in the art would be motivated to use the lower amounts similar to Shimizu to treat neuropathic pain and expected that the lower dose of Shimizu to not be neurotoxic. Additionally, risks are inherent in medicine and one of ordinary skill in the art would at least try similar low doses of lithium chloride to see if the potential benefits (e.g., treat neuropathic pain) outweigh those risks.
Thus, for the reasons of record and for the reasons presented above claims 63-74 and 76-89 are rejected under 35 U.S.C. 103(a).
Conclusion and Correspondence
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN P NGUYEN whose telephone number is (571)270-5877. The examiner can normally be reached Monday-Friday 10am-6pm EST.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600
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