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 .
DETAILED ACTION
The amendment dated 22 January 2026, in which claim 1 has been amended, and claims 17, 22, 23 have been cancelled, is acknowledged.
Claims 1-8, 11-16, 18-20 are pending in the instant application.
Claims 2-6, 8, 18, 19 are withdrawn, as being drawn to a non-elected species.
Claims 1, 7, 11-16, 20 are examined herein.
Response to arguments of 22 January 2026
In view of Applicant’s amendment of 22 January 2026, all the objection and rejections to claims 17, 22, 23 are herein withdrawn. Claims 17, 22, 23 have been cancelled.
In view of Applicant’s amendment of 22 January 2026, the objection to claims 2-6 is herein withdrawn. The status indicators have been corrected.
On 22 January 2026, Applicant has amended independent claim 1 to recite that the PPARbeta agonist administered in the method is KD3010.
In view of Applicant’s amendment of 22 January 2026, the rejection of claims 1, 12, 14, 15, 17, 22, 23 under 35 U.S.C. 102(a)(1) over Polak; the rejection of claims 1, 12, 14, 15, 16, 17, 20, 22, 23 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Chandross; the rejection of claims 1, 12, 14 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Keil et al.; the rejection of claims 1, 12, 14, 15, 16 under 35 U.S.C. 102(a)(1) and 102(a)(2) over McGarry et al. (US 2007/0060626); the rejection of claims 1, 12, 14, 15, 16 under 35 U.S.C. 102(a)(1) and 102(a)(2) over McGarry et al. (US 2007/0099964); and the rejection of claims 1, 12, 14, 15, 16 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Bernardelli et al., are herein withdrawn.
Applicant’s arguments (Remarks of 22 January 2026, pages 7-10) against the rejection of claims 1, 7, 11-17, 20, 22, 23 under 35 U.S.C. 103 over Chandross, in view of Ghanbari, in further view of Dickey and Negrin, have been considered.
Applicant argues (page 8, third paragraph) lack of motivation to combine KD3010's use in Huntington's disease (Dickey) with demyelination teachings from Chandross and the chemotherapy context of Ghanbari/Negrin.
This argument is not persuasive. Chandross teaches that selective PPARdelta agonists (also known as PPAR beta agonists) are effective to treat CNS de-myelinating diseases, and
Dickey teaches that KD3010 is a highly selective, potent and brain penetrant PPARdelta agonist.
Based on the combined teachings of Chandross and Dickey, a person of ordinary skill in the art would have been motivated to administer selective, potent and brain penetrant PPARdelta agonist KD3010 in a method of treating a CNS de-myelinating disease, with a reasonable expectation of success.
Applicant has not shown the unpredictability in the field- that not all selective, potent and brain penetrant PPARdelta agonists are effective to treat a CNS de-myelinating disease such as chemotherapy induced demyelination and associated cognitive dysfunction. The examiner notes the last two sentences in the first paragraph, on page 9, Remarks of 22 January 2026; yet, Applicant has not explained how the instant compound KD3010 is distinct in terms of selectivity, agonism, BBB penetration over other PPAR delta agonists disclosed by Chandross, or whether some unexpected result is achieved with KD3010 versus other PPARdelta agonists disclosed by Chandross in treating a demyelinating disease.
Applicant argues (page 8, third paragraph) that Dickey is focused exclusively on Huntington's disease, and does not address demyelination, dysmyelination, myelin lipid dysfunction, or Qki-dependent lipid metabolism, and a skilled artisan would have no reason to take KD3010 from a neuronal-loss disorder and apply it to chemotherapy-induced demyelination. This is not persuasive. Dickey is used in the rejection for the teaching that KD3010 is a highly selective, potent and brain penetrant PPARdelta agonist.
Applicant argues (page 8, last paragraph, page 9, first paragraph) that the cited references do not provide a reasonable expectation of success for the claimed results. Applicant focusses the argument on the mechanism recited in instant claim 1, namely restoring Qki- dependent lipid metabolism in myelin with a PPARdelta agonist KD3010.
This argument is not persuasive, because the instant claims are drawn to a method of treating a demyelinating disease with PPAR delta agonist KD3010, and PPARdelta agonists were known to be effective to treat a demyelinating disease.
Applicant’s argument (page 9, first paragraph) that Chandross only speculates that PPAR delta agonists would be expected to stimulate myelin formation in vivo, is not persuasive. Contrary to Applicant’s argument, Chandross does not speculate; Chandross clearly teaches (Abstract, [0016]) a method for treating a demyelinating disease in a patient in need thereof comprising administering to the patient an effective amount of a PPAR delta (also known as PPARb [0004]) agonist, as in instant claim 1. Chandross teaches that demyelinating diseases treated by this method include multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome and disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury; adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, tropical spastic paraparesis, as well as acute conditions in which demyelination can occur in the CNS, e.g., acute disseminated encephalomyelitis (ADEM), acute viral encephalitis and acute transverse myelitis.
Chandross clearly teaches that selective PPAR delta (also known as PPARb [0004]) agonists
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L-165,041 [0014], are effective to treat [0031] multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome and disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury.
Thus, Chandross teaches beyond speculation that PPAR delta agonists are effective to treat a variety of demyelinating diseases.
Chandross also teaches [0170] that the PPAR delta agonists above enhance or accelerate rat and human oligodendrocyte differentiation, as measured by increased myelin basic protein expression compared to untreated controls. Chandross teaches that selective PPAR delta agonists enhance, accelerate, or stimulate oligodendrocyte differentiation and myelin formation in vivo, in the diseased or injured CNS, including MS and other demyelinating disorders.
Applicant argues that Chandross’s speculation that PPAR delta agonists are expected to stimulate myelin formation in vivo is insufficient to support a reasonable expectation that administering KD3010 to a patient with chemotherapy-induced demyelination would increase myelin lipid levels or restore a specific Qki- dependent lipid program in myelin. This argument is not persuasive. The point is not whether KD3010 increases myelin lipids; rather, the point is that Chandross clearly teaches that PPAR delta agonists are effective to treat a variety of demyelinating diseases. This teaching in Chandross, combined with the knowledge that KD3010 is a potent, selective and brain penetrant PPAR delta agonist (Dickey), provides the motivation to administer KD3010 to a subject suffering from a demyelinating disease, with a reasonable expectation of achieving therapeutic effect. Claim 1 is drawn to a method of treating a demyelinating disease with KD3010. Measuring levels of myelin lipids in the patient prior, during and after treatment is within the skill of the artisan.
Applicant argues (page 9, last two paragraphs) that Chandross is speculative with respect to in vivo myelin repair and does not teach the myelin lipid restoration limitations of amended claim 1. This argument has been addressed above.
Applicant argues (page 9, last paragraph, page 10) that none of the cited references, alone or in any combination, teach or suggest the key mechanistic limitation in claim 1, restoration of Qki-PPARd-RXRa-dependent lipid metabolism in myelin, nor do they teach that KD3010 (or any PPARdelta agonist) increases myelin lipids in a patient with dysmyelinating/demyelinating disease or condition. Applicant argues that the claimed increase in myelin lipids and/or restoration of Qki-PPARd-RXRa-dependent lipid metabolism constitutes a non-predictable, unexpected result for KD3010 in dysmyelinating/demyelinating disease, and cannot be obtained through routine optimization of the cited art. In response, as explained above, claim 1 is drawn to a method of treating a demyelinating disease with KD3010. Based on the combination of teachings of Chandross and Dickey, a POSITA would be motivated to administer KD3010 to a subject suffering from a demyelinating disease, with a reasonable expectation of achieving therapeutic effect. Since the PPARdelta agonists were known to be effective to treat a CNS demyelinating disease, determining the mechanism by which said PPAR delta agonists work in the method of treatment will not render the method unobvious because such claimed increase in the levels of myelin in the patient, or such restoring Qki-PPARbeta-RXRalpha-dependent lipid metabolism in myelin would necessarily occur upon administering a PPARdelta agonist to a subject suffering from a demyelinating disease.
For all these reasons, the rejection of claims 1, 7, 11-17, 20, 22, 23 under 35 U.S.C. 103 over Chandross, in view of Ghanbari, in further view of Dickey and Negrin, is maintained, a modified rejection is made below, based on Applicant’s amendment of 22 January 2026.
As indicated in the non-final rejection mailed on 22 July 2025, the claims have been examined to the extent they read on the elected species: chemotherapy induced demyelination as a specific demyelinating disease to be treated; and KD3010 as a specific PPARb agonist administered in the method of treatment, and the following objections and rejections are made below.
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, 7, 11-16, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Chandross et al. (US 2007/0149580, cited in PTO-892 of 22 July 2025), in view of Ghanbari et al. (US 2016/0235725, cited in PTO-892 of 22 July 2025), in further view of Dickey et al. (Nature Medicine 2016, 22 (1), 37-47, cited in PTO-892 of 22 July 2025), and Negrin et al. (Patient education: hematopoietic cell transplantation (bone marrow transplantation) (Beyond the basics) 2017, 28 February (cited in IDS).
Chandross teaches (Abstract, [0016]) a method for treating a demyelinating disease in a patient in need thereof comprising administering to the patient an effective amount of a PPAR delta (also known as PPARb [0004]) agonist, as in instant claim 1. Demyelinating diseases that may be effectively treated by this method include but are not limited to multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome and disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury.
Chandross teaches [0007] that central demyelination (demyelination of the CNS), as in instant claim 14, occurs in several conditions, often of uncertain etiology, that have come to be known as the primary demyelinating diseases; of these, multiple sclerosis is the most prevalent. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, tropical spastic paraparesis, as well as acute conditions in which demyelination can occur in the CNS, e.g., acute disseminated encephalomyelitis (ADEM), acute viral encephalitis and acute transverse myelitis.
Chandross teaches that selective PPAR delta (also known as PPARb [0004]) agonists
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L-165,041 [0014], which is a compound of instant claim 17, are effective to treat [0031] multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome and disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury, which is consistent with the PPAR delta agonists above being effective to reduce severity of neurological deficits in the patient, as in instant claim 12, and is consistent with the PPAR delta agonists above being able to cross the blood brain barrier (to treat CNS demyelinating diseases), as in instant claim 15, and able to penetrate the peripheral nervous system, as in instant claim 16.
Chandross teaches [0170] that the PPAR delta agonists above enhance or accelerate rat and human oligodendrocyte differentiation, as measured by increased myelin basic protein expression compared to untreated controls. This novel finding would suggest that compound 1 and compound 2 and selective PPAR delta agonists in general would be enhance, accelerate, or stimulate oligodendrocyte differentiation and myelin formation in vivo, in the diseased or injured CNS, including MS and other demyelinating disorders.
Chandross teaches [0170] that the PPAR delta agonists above promote oligodendrocyte differentiation ([0194], Fig. 1-6) even in the presence of mitogens, which normally keep cells mitotically active and inhibit cellular differentiation. Thus, it is expected that in the injured or diseased CNS selective PPAR delta agonists will cause dividing oligodendrocyte progenitor cells to express myelin proteins and ensheath demyelinated or hypomyelinated axons, as in instant claim 20.
Chandross does not teach that the demyelinating condition to be treated with a PPARdelta/beta agonist is chemotherapy-induced demyelination or chemotherapy-induced cognitive dysfunction (Applicant’s elected species of a demyelinating disease), as in instant claim 11.
Chandross does not teach that the PPARdelta agonist administered in the method of treatment is KD3010 (Applicant’s elected species), as in the instant claims.
Chandross does not teach the method, further comprising performing hematopoietic bone marrow transplantation on the patient, as in instant claim 7.
Ghanbari (US 2016/0235725) teaches the link between chemotherapy, and its most common complications, namely chemotherapy-induced cognitive impairment, chemotherapy-induced cognitive dysfunction, post-chemotherapy cognitive impairment (PCCI), chemo fog, or chemo brain [0001], and damage to myelinated tracts of the CNS. Ghanbari teaches [0002] that short-term systemic administration of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent, caused progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology.
Dickey et al. (Nature Medicine 2016, 22 (1), 37-47) teaches (page 43, right column, last paragraph) that KD3010 ((S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1- sulfonyl]-indan-2-carboxylic acid tosylate, Applicant’s elected species) is a highly selective, potent and brain penetrant PPAR-δ agonist.
Dickey teaches that intraperitoneal (i.p.) injection of KD3010 (15 mg per kg of body weight (mg/kg)) into C57BL/6J mice resulted in a ratio of KD3010 in the brain to KD3010 in the plasma of ~10% at 2- to 24-h after injection. Dickey teaches (page 43, right column, last paragraph) that KD3010 treatment (50 mg/kg per day i.p.) induced the expression of PPAR-δ target genes in the brains of living mice.
Negrin et al. (Patient education: hematopoietic cell transplantation (bone marrow transplantation) (Beyond the basics) 28 February 2017 (cited in IDS) teaches hematopoietic bone marrow transplantation in patients undergoing chemotherapy. Negrin teaches (page 1) that chemotherapy is toxic to the bone marrow.
It would have been obvious to a person of ordinary skill in the art to combine the teachings of Chandross, Ghanbari and Dickey to arrive at the instant invention. The person of ordinary skill in the art would have been motivated to administer KD3-010 in a method of treating chemotherapy induced demyelination and associated cognitive dysfunction, because Chandross teaches that selective PPARdelta agonists (also known as PPAR beta agonists) are effective to treat CNS de-myelinating diseases,
Ghanbari teaches that chemotherapy-induced demyelination and chemotherapy-induced cognitive dysfunction are CNS-de-myelinating diseases, and
Dickey teaches that KD3010 (Applicant’s elected species) is a highly selective, potent and brain penetrant PPARdelta agonist.
Thus, the person of ordinary skill in the art would have administered selective and brain penetrant PPARdelta agonist KD3010 to treat CNS demyelination and cognitive impairment due to chemotherapy, with the expectation that KD3010 is effective to treat CNS demyelination caused by chemotherapy and its symptom, chemotherapy induced cognitive impairment.
Further, regarding claim 7, the person of ordinary skill in the art would have performed the method in a patient who undergoes hematopoietic bone marrow transplant, because chemotherapy is known to be toxic to bone marrow, as taught by Negrin, and chemotherapy patients are known to undergo hematopoietic bone marrow transplant.
Even though the references cited do not specifically teach that the method increases the level of myelin lipids in the patient, or that the method restores Qki-PPARb-RXRa-dependent lipid metabolism in myelin, as in instant claims, the ability to increase the level of myelin lipids, or to restore Qki-PPARb-RXRa-dependent lipid metabolism in myelin in a patient upon administration, are inherent properties of the PPARd/b agonist KD3010. In the instant case, increasing the level of myelin lipids in the patient, or restoring Qki-PPARb-RXRa-dependent lipid metabolism in myelin, are inherently associated with treatment of a demyelinating disease by administering PPARd/b agonist KD3010.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. See MPEP 2145.II. In this case, the closest prior art, Chandross (used in combination with Ghanbari and Dickey), teaches (Abstract, [0016]) that PPAR delta (also known as PPARbeta) agonists are effective to treat a CNS demyelinating disease in a patient in need thereof. Since the PPARdelta/beta agonists were known to be effective to treat a CNS demyelinating disease, determining the mechanism by which said PPAR delta/beta agonists work in the method of treatment, will not render the method unobvious because such claimed increase in the levels of myelin in the patient, or such restoring Qki-PPARbeta-RXRalpha-dependent lipid metabolism in myelin would necessarily occur upon administering a PPARdelta/beta agonist to a subject suffering from a demyelinating disease.
As such, claims 1, 7, 11-16, 20 are rejected as prima facie obvious.
Conclusion
Claims 1, 7, 11-16, 20 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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