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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/12/2025 has been entered.
Election/Restrictions
Applicant’s election of compound
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in the reply filed on 08/15/2024 is maintained.
Priority
This application is a U.S. national stage filing under 35 U.S.C. § 371 from International Application No. PCT/US2020/023697, filed on March 19,2020, and published as W02020/191227 Al on September 24, 2020, which claims benefit of priority to the filing date of U.S. Provisional Application Ser. No. 62/821,167, filed March 20, 2019.
Claim Status
Claims 1-27 are pending. Claims 7 and 8 are withdrawn. Claims 1-6 and 9-27 are examined in accordance to the elected species.
Action Summary
Claim 1-6 and 9-27 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the claim amendment.
Claims 1-6, 9-20, and 22-27 rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al (US2017/0253590A1) in view of Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16) and Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), are withdrawn in light of claim amendment.
Claims 1-6 and 9-27 rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al (US2017/0253590A1) in view of Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16) and Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), as applied to claims 1-6, 9-20, and 22-27 in further view of Pavlin et al (Anesth Analg. 2002 Sep;95(3):627-34), are withdrawn in light of the claim amendment.
Claims 1-6, 9-20, and 22-27 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,125,123 B2 in view of Glimcher et al (US2017/0253590A1), Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16, Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), are maintained.
Claims 1-6, 9-20, and 22-27 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,988,846 B2 in view of Glimcher et al (US2017/0253590A1), Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16, Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), are mantained.
Affidavit
The Declaration by Cubillos Ruiz under 37 CFR 1.132 filed 11/12/2025 is insufficient to overcome the rejection of claims 1-6 and 9-27.
The Declarant argues that Glimcher does not suggest or otherwise contemplate treating analgesia or pain endpoints in humans for any IRE1 inhibitors, let alone the specific compounds
disclosed. Further, Liu' s teachings are strictly about reversing morphine tolerance, nothing more. To be sure, Liu in no way contemplates de nova analgesia. Liu' s interventions are intrathecal, target neuronal/astrocytic UPR signaling, and are designed to preserve opioid efficacy, not replace it. At no point does Liu show that an IRE1 inhibitor reduces pain in opioid naive subjects or modulates peripheral myeloid eicosanoids. See Liu abstract. What Liu actually shows is that morphine tolerance, which is the loss of opioid efficacy after repeated dosing, correlates with UPR activation in the spinal cord, and that intrathecal inhibition of UPR. arms attenuate tolerance.
Examiner’s response.
In response, the Declarant’s argument is not persuasive. The Examiner does not dispute that that Glimcher does not suggest or otherwise contemplate treating analgesia or pain endpoints in humans for any IRE1 inhibitors, let alone the specific compounds
disclosed. The Examiner does not dispute also that at no point does Liu show that an IRE1 inhibitor reduces pain in opioid naive subjects or modulates peripheral myeloid eicosanoids. However, the Examiner contends that Glimcher clearly teaches compound 81 can be used to treat inflammation and other disease. Liu clearly teaches pain is caused by the activation of ER stress sensors such as IRE1α and the fact that inhibition of said ER stress sensor such as IRE1α can restore the antinociceptive effect of morphine and other pain. Omoigui teaches that all pain arises from inflammation. Therefore, one would reasonably expect the method taught by Glimcher to include pain or inflammatory pain, or pain-induced by morphine tolerance.
The Declarant’s argument
The Declarant argues that even if Liu had shown that STF 083010 induced analgesia as the Patent Office appears to believe-those of ordinary skill in the art would not have used STF 083010 as a starting point at least because of the stark structural dissimilarities between STF 083010 and the compounds described in the captioned application and the fact that STF 083010 was not shown to induce analgesia. Because the elected series (heteroaryl urea with a basic amine and CF3-aryl) differs fundamentally from STF- 083010's planar, neutral phenolic
sulfone, the SAR for IRE la inhibition is non-transferable and the spinal, intrathecal UPR effects of STF-083010 do not forecast the systemic peripheral myeloid engagement and selective Cox-2mPGES-1 suppression achieved by the elected species.
Examiner’s response.
In response, the Declarant’s argument is not persuasive. It may well be true that STF 083010 has a different structure than the compound 81 of Gimcher. However, both compounds have IRE1-α inhibitors. Again, the fact that Liu teaches Pain is caused by the activation of ER stress sensors such as IRE1α and the fact that inhibition of said ER stress sensor such as IRE1α can restore the antinociceptive effect of morphine, and the fact that Liu teaches STF 083010 an inhibitor of IRE1α induced analgesia, one would reasonably expect compound 81 having IRE1α inhibiting action to effectively reduce the development of morphine tolerance and by reducing morphine tolerance, morphine can effectively treat pain. Lastly, prostaglandin-endoperoxide synthase 2 and prostaglandin E synthase are not recited in the claim. The recitations of reductions of prostaglandin-endoperoxide synthase 2 and prostaglandin E synthase in claim 11, reductions in PGE2 in myeloid cells (claim 15), and no effect on PTGS1 (COX 1) or PGES2 plus absence of GI side effects (claim 22) appear to be the intended outcome of the administration step positively recited and would naturally flow from the fact that compound 81 can effectively treat inflammation.
The Declarant’s argument
The Declarant argues that even if combined with Glimcher, Liu, and/or Omoigui, does not undermine the patentability of the claims. To be sure, Pavlin does not undermine the patentability of claims that quantify pain by ambulatory counts/time resemble preclinical locomotor/mobility metrics (e.g., open field counts) (e.g., claim 21). The Office Action's reliance on Pavlin for the teaching that "pain complicates the recovery process after ambulatory surgery" (Office Action at page 11) does not actually teach the specific quantitative metrics recited in, for example, claim 21. At most, Pavlin shows clinicians care about ambulation after surgery. But Pavlin does not disclose "number of ambulatory counts per selected time period'' or "total ambulatory time per time per time period” That gap remain
Examiner’s response.
In response, the Declarant’s argument is not persuasive because Pavlin clearly teaches 175 ambulatory surgery patients to determine pain severity which meets the number of ambulatory counts per selected time period.
Improper Markush Grouping Rejection
Claims 1-6 and 9-27 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the formula (I)
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or the formula (II)
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is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Specifically, ring A or B which can be hetercyclyl ring including imidazopyridine
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having hypnotic activity and a phenyl ring having antifungal, anti-tumor and enzymatic properties.
Ring C can be a phenyl ring or a pyridinyl ring. Pyridinyl ring
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which can be used in agrochemical industries. Ring D can be a piperazine ring
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having antihemmintic properties.
Therefore, the members of the Markush grouping are not considered to share a “single structural similarity” and common use where the alternatives do not share both a substantial structural feature and a common use because the ethanolamine does not constitute a significant portion of the Etn-related compound.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 non-obviousness.
Claims 1-6, 9-20, and 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al (US2017/0253590A1) in view of Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16), Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), Gui et al (Anesth Analg. 2018 Sep;127(3):775-783), and Lin et al (J. Pharmacol. Exp. Ther. 355, 496–505, March 6, 2018).
Glimcher teaches of a method for treating or reducing cancer, comprising: administering to a subject in need thereof, the compound of the formula Ia. (See claims 19 and 39.) Moreover, Glimcher teaches the compound is compound 81
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as one of the exemplified or preferred compound of the formula Ia. (See page 25 r table 4.) This compound reads on the elected compound:
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. Moreover, Glimcher teaches these compounds are IRE1α inhibitors and can be formulated in a pharmaceutically composition. (See Abstract.) The compounds of the invention can be administered to a human in need of such treatment, prevention, elimination, alleviation or amelioration of a mal-condition that is mediated through the action of IRElα, for example, cancer, neurodegenerative diseases, inflammation, metabolic disorders, liver dysfunction, brain ischemia, or heart ischemia. (See paragraph [0172].) Furthermore, Glimcher teaches the compounds can be used in the amount of 0.05 mg to about 1,000 mg together with a pharmaceutically acceptable carrier and administered daily or more than once a day, twice or thrice daily. (See paragraphs [0175] and [0177].) The compound or the pharmaceutical composition can generally be administered in the form of a dosage unit in an amount of 1 ng/kg of body weight to about 0.5 g/kg of body weight. (See paragraph [0173].)
Glimcher does not teach the condition is pain.
Liu teaches endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, and a significant driver of morphine tolerance. Chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. (See Abstract.) Moreover, Liu teaches previous studies have shown that ER stress and subsequent UPR were involved in obesity, heart disease, ischemia/reperfusion injury, diabetes, atherosclerosis, cancer, Alzheimer’s disease and Parkinson’s disease, as well as various types of chronic pain, including DPN, orofacial inflammatory pain, and neuropathic pain. Binding immunoglobulin protein (BiP) is a central player in ER homeostasis. Under physiological conditions, BiP is associated with the ER stress sensors IRE1, PERK, and ATF6. When ER stress occurs, BiP dissociates from ER stress sensors and binds to misfolded proteins, resulting in the activation of three branches of UPR. (See page 10, left column bridging right column.) Lie also teaches in a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain, the ER stress and UPR pathways were significantly activated. (See second paragraph of the right column of page 11.)
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
Gui teaches in this study, CCI (chronic constriction injury) surgery significantly induced mechanical allodynia and thermal hyperalgesia. CCI surgery significantly induced activation of ER stress (PERK-eIF2α, IRE1α, CHOP, and XBP-1s) in rats. (See Abstract.)
Lin provides the first direct evidence that ER stress is a significant driver of OIH (opioids-induced hyperalgesia). GRP78, the ER stress marker, is markedly upregulated in neurons in the spinal cord after chronic morphine treatment. At the same time, morphine induces the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1), protein kinase RNAlike ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). Notably, we found that inhibition on either IRE1α/XBP1 or ATF6, but not on PERK/eIF2α could attenuate the development of OIH. (See Abstract.)
The fact that Liu teaches Pain is caused by the activation of ER stress sensors such as IRE1α and the fact that inhibition of said ER stress sensor such as IRE1α can restore the antinociceptive effect of morphine and other pain and the fact that all pain arises from inflammation, it would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to modify the method taught by Glimcher to include pain or inflammatory pain, or to include morphine to the administration of compound 81 for allowing morphine to treat pain to give Applicant’s claimed method. The motivation to do so, is because Glimcher teaches compound 81 as one of the IRE1α inhibitors that can be used to treat the condition that is mediated through the action of IRElα and because Liu teaches taught by Glimcher Pain is caused by the activation of ER stress sensors such as IRE1α and inhibition of said ER stress sensor such as IRE1α can restore pain, because Omoigui teaches all pain arises from inflammation and the inflammatory response, because Gui teaches in this study, CCI (chronic constriction injury) surgery significantly induced mechanical allodynia and thermal hyperalgesia and CCI surgery significantly induced activation of ER stress (PERK-eIF2α, IRE1α, CHOP, and XBP-1s) in rats, and lastly because Lin found that inhibition on either IRE1α/XBP1 or ATF6, but not on PERK/eIF2α could attenuate the development of OIH (opioids-induced hyperalgesia). One would reasonably expect the method taught by Glimcher to successfully treat or reduce pain, pain resulted from morphine tolerance, or inflammatory pain.
With respect to the following limitations:
“the composition reduces prostaglandin endoperoxide synthase 2 (Ptgs2/Cox-2) expression in cells of the subject by a least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%” of claim 11;
“the composition reduces prostaglandin E synthase (Ptges/mPGES-1) expression in cells of the subject by a least 5%” of claim 12;
“the composition does not affect expression of prostaglandin-endoperoxide synthase 1 in cells of the subject” of claim 13;
“the composition does not affect expression of or prostaglandin E synthase 2 in cells of the subject, wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14 and 15;
“the composition reduces concentrations of one or more prostaglandin, arachidonic acid, or a combination thereof in cells of the subject by a least 5%, wherein the prostaglandin is PGE1, 15-keto PGF2a,
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D12-PGJ2 PGD3, PGE2, PGF2a, 13,14dh-15k PGE2, PGD2, PGD3, PGF1ca, or a combination thereof, and wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14, 16, and 19;
“the composition reduces concentrations of PGE2 in cells of the subject” of claim 18;
“the pain is reduced in the subject by a least 5%” of claim 20;
“the composition does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 22; and
“the subject does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 23; said limitations are the characteristics or outcome of the method. The claimed characteristics or outcome of the method would flow naturally from the obvious method of the collective teachings of Glimcher and Liu. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Claims 1-6 and 9-27 are rejected under 35 U.S.C. 103 as being unpatentable over Glimcher et al (US2017/0253590A1) in view of Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16) and Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28), Gui et al (Anesth Analg. 2018 Sep;127(3):775-783), and Lin et al (J. Pharmacol. Exp. Ther. 355, 496–505 March 6, 2018), as applied to claims 1-6, 9-20, and 22-27 in further view of Pavlin et al (Anesth Analg. 2002 Sep;95(3):627-34).
The teachings of Glimcher, Liu, Omoigui, Gui, and Lin have been discussed in the rejection set forth above.
Glimcher, Liu, Omoigui, Gui, and Lin collectively do not teach the pain is measured by the subject's number of writhings per selected time-period, the number of changes in weight distribution per selected time-period, the number of ambulatory counts per selected time-period, the total ambulatory time per time-period, or a combination thereof.
Pavlin teaches pain complicates the recovery process after ambulatory surgery.175 ambulatory surgery patients to determine pain severity, analgesic use, relationship of pain to duration of recovery, and the relative importance of various factors to predicting these outcomes were surveyed. Moderate to severe pain is common after ambulatory surgery and is a frequent cause of delayed discharge. Postoperative pain, opioid-related side effects, and time to discharge were less when nonsteroidal anti-inflammatory drugs or local anesthetics were used intraoperatively to prevent pain before patient awakening. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the obvious method taught Glimcher, Liu Omoigui, Gui, and Lin by measuring the pain by the number of ambulatory counts per selected time-period, or by the total ambulatory time per time-period to give Applicant’s claimed method. One would have been motivated by the fact that Pavlin teaches moderate to severe pain is common after ambulatory surgery and is a frequent cause of delayed discharge. Postoperative pain, opioid-related side effects, and time to discharge were less when nonsteroidal anti-inflammatory drugs or local anesthetics were used intraoperatively to prevent pain before patient awakening. (See Abstract.) One would have a reasonable expectation of success to measure the pain by the number of ambulatory counts per selected time-period, or by the total ambulatory time per time-period to successfully improve patient’s compliance and to reduce the time to discharge.
Applicant’s argument with respect to the Declaration has been addressed in the Affidavit section above.
Applicant’s argument
Applicant argues that though Liu may investigate IREI/XBP they do so strictly in the context of whether spinal IREi/XBP plays a role in the development of morphine tolerance. As the Patent Office notes, the experiments described at pages 6 and 7 of Liu "suggest that activation of spinal IRE1/XBPI cascade in neurons and astrocytes might be involved in the development of morphine tolerance." And even though Liu may state that dissociation of BiP may result in the "activation of three branches of UPR," there is no evidence-certainly none that the Patent Office has adduced--that inhibition of any one of them might provide the reasonable expectation of reducing pain. In sum, even if one takes the teachings of Liu in their entirety, one cannot conclude that inhibition of IREI would be effective in reducing pain. And for this reason, Glimcher, even in view of Liu, does riot render the claimed invention obvious. Further, Pavlin does not remedy the deficiencies in Glimcher and Liu. Applicant therefore respectfully requests reconsideration and withdrawal of the rejection of claims 1-6, 9-20 and 22-27 over Glimcher and Liu; and claims 1-6 and 22-27 over Glimcher, Liu, and Pavlin.
Examiner’s answer
In response, Applicant’s argument is not persuasive. It may well be true that Liu relates IRE1/XBP1 in the context of whether IRE1/XBP1 plays a pivotal role in the development of morphine tolerance. Liu also teaches in an attempt to restore the intracellular homeostasis, ER stress could lead to the activation of UPR, which is mediated by three ER stress sensors and related signaling pathways: IRE1, PERK and ATF6. Under physiological conditions; ER stress sensors are kept in the inactive state through being bound by chaperone BiP (binding immunoglobuin protein). However, BiP could dissociate from the sensors when ER stress occurs, resulting in the activation of UPR. ER stress has been reported to play a fundamental role in the pathogenesis of many diseases including neurodegenerative disorders, metabolic syndrome, cardiovascular diseases and cancer. And it might also be involved in the induction and maintenance of neuropathic pain and inflammatory pain. (See second paragraph of the left column of page 2.) Moreover, Liu teaches in a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain, the ER stress and UPR pathways were significantly activated. Moreover, the activation of ER stress was detected in the peripheral nervous system of diabetic nephropathy rats. Interestingly, chemical inducers of ER stress could lead to pain behavior which can be reversed by a chemical chaperone. An early activation of UPR pathways could be detected after SCI (spinal cord injury). Moreover, SCI could lead to the up-regulation of several key ER stress response genes (e.g., ATF4, GADD34, GRP78, and CHOP) at the injury epicenter. (See left column of page 11.) Furthermore, Omoigui teaches the original of all pain is inflammation and inflammatory responses. Therefore, a person of ordinary skill in the art would reasonably expect the IRE1/XBP1 inhibitors including compound 81 for treating inflammation taught by Glimcher to successfully be effective for reducing pain or inflammatory pain by inhibiting or inactivating/deactivating IRE1/XBP1 or by treating inflammation.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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 1-6, 9-20, and 22-27 remain rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,125,123 B2 in view of Glimcher et al (US2017/0253590A1), Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16, Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28),
The U.S. patent claims teach A compound of formula Ia:
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. (See claim 1.) Moreover, the U.S. patent claims teach
The following compounds:
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. (See claim 10.)
The U.S. patent claims do not teach the elected compound.
Glimcher teaches of a method for treating or reducing cancer, comprising: administering to a subject in need thereof, the compound of the formula Ia. (See claims 19 and 39.) Moreover, Glimcher teaches the compound is compound 81
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as one of the exemplified or preferred compound of the formula Ia. (See page 25 r table 4.) This compound reads on the elected compound:
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. Moreover, Glimcher teaches these compounds are IRE1α inhibitors and can be formulated in a pharmaceutically composition. (See Abstract.) The compounds of the invention can be administered to a human in need of such treatment, prevention, elimination, alleviation or amelioration of a mal-condition that is mediated through the action of IRElα , for example , cancer , neurodegenerative diseases , inflammation , metabolic disorders , liver dysfunction , brain ischemia , or heart ischemia .. (See paragraph [0172].) Furthermore, Glimcher teaches the compounds can be used in the amount of 0.05 mg to about 1,000 mg together with a pharmaceutically acceptable carrier and administered daily or more than once a day, twice or thrice daily. (See paragraphs [0175] and [0177].) The compound or the pharmaceutical composition can generally be administered in the form of a dosage unit in an amount of 1 ng/kg of body weight to about 0.5 g/kg of body weight. (See paragraph [0173].)
Liu teaches endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, and a significant driver of morphine tolerance. Chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. (See Abstract.) Moreover, Liu teaches previous studies have shown that ER stress and subsequent UPR were involved in obesity, heart disease, ischemia/reperfusion injury, diabetes, atherosclerosis, cancer, Alzheimer’s disease and Parkinson’s disease, as well as various types of chronic pain, including DPN, orofacial inflammatory pain, and neuropathic pain. Binding immunoglobulin protein (BiP) is a central player in ER homeostasis. Under physiological conditions, BiP is associated with the ER stress sensors IRE1, PERK, and ATF6. When ER stress occurs, BiP dissociates from ER stress sensors and binds to misfolded proteins, resulting in the activation of three branches of UPR. (See page 10, left column bridging right column.) Lie also teaches in a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain, the ER stress and UPR pathways were significantly activated. (See second paragraph of the right column of page 11.)
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
It would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to select the compound 81 of Glimcher out of the list of compounds of the U.S patent claims and use said compound to treat pain to give Applicant’s claimed method. The motivation to do so, is because Glimcher teaches compound 81 as one of the IRE1α inhibitors that can be used to treat the condition that is mediated through the action of IRElα and because Liu teaches taught by Glimcher Pain is caused by the activation of ER stress sensors such as IRE1α and inhibition of said ER stress sensor such as IRE1α can restore pain, and also because Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.). One would reasonably expect the modified compound to successfully treat or reduce pain or inflammatory pain.
With respect to the following limitations:
“the composition reduces prostaglandinendoperoxide synthase 2 (Ptgs2/Cox-2) expression in cells of the subject by a least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%” of claim 11;
“the composition reduces prostaglandin E synthase (Ptges/mPGES-1) expression in cells of the subject by a least 5%” of claim 12;
“the composition does not affect expression of prostaglandin-endoperoxide synthase 1 in cells of the subject” of claim 13;
“the composition does not affect expression of or prostaglandin E synthase 2 in cells of the subject, wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14 and 15;
“the composition reduces concentrations of one or more prostaglandin, arachidonic acid, or a combination thereof in cells of the subject by a least 5%, wherein the prostaglandin is PGE1, 15-keto PGF2a,
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D12-PGJ2 PGD3, PGE2, PGF2a, 13,14dh-15k PGE2, PGD2, PGD3, PGF1ca, or a combination thereof, and wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14, 16, and 19;
“the composition reduces concentrations of PGE2 in cells of the subject” of claim 18;
“the pain is reduced in the subject by a least 5%” of claim 20;
“the composition does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 22; and
“the subject does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 23; said limitations are the characteristics or outcome of the method. The claimed characteristics or outcome of the method would flow naturally from the obvious method of the collective teachings of Glimcher and Liu. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Claims 1-6, 9-20, and 22-27 remain rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,988,846 B2 in view of Glimcher et al (US2017/0253590A1), Liu et al (Front. Mol. Neurosci., 05 March 2018, volume 11, article 72, [ages 1-16, Omoigui et al (Med Hypotheses. 2007;69(6):1169-78. Epub 2007 Aug 28).
The U.S. patent claims teach
. A compound of formula I,
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. (See claim 1.)
The U.S. patent claims do not teach the elected compound.
Glimcher teaches of a method for treating or reducing cancer, comprising: administering to a subject in need thereof, the compound of the formula Ia. (See claims 19 and 39.) Moreover, Glimcher teaches the compound is compound 81
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as one of the exemplified or preferred compound of the formula Ia. (See page 25 r table 4.) This compound reads on the elected compound:
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. Moreover, Glimcher teaches these compounds are IRE1α inhibitors and can be formulated in a pharmaceutically composition. (See Abstract.) The compounds of the invention can be administered to a human in need of such treatment, prevention, elimination, alleviation or amelioration of a mal-condition that is mediated through the action of IRElα , for example , cancer , neurodegenerative diseases , inflammation , metabolic disorders , liver dysfunction , brain ischemia , or heart ischemia .. (See paragraph [0172].) Furthermore, Glimcher teaches the compounds can be used in the amount of 0.05 mg to about 1,000 mg together with a pharmaceutically acceptable carrier and administered daily or more than once a day, twice or thrice daily. (See paragraphs [0175] and [0177].) The compound or the pharmaceutical composition can generally be administered in the form of a dosage unit in an amount of 1 ng/kg of body weight to about 0.5 g/kg of body weight. (See paragraph [0173].)
Liu teaches endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, and a significant driver of morphine tolerance. Chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. (See Abstract.) Moreover, Liu teaches previous studies have shown that ER stress and subsequent UPR were involved in obesity, heart disease, ischemia/reperfusion injury, diabetes, atherosclerosis, cancer, Alzheimer’s disease and Parkinson’s disease, as well as various types of chronic pain, including DPN, orofacial inflammatory pain, and neuropathic pain. Binding immunoglobulin protein (BiP) is a central player in ER homeostasis. Under physiological conditions, BiP is associated with the ER stress sensors IRE1, PERK, and ATF6. When ER stress occurs, BiP dissociates from ER stress sensors and binds to misfolded proteins, resulting in the activation of three branches of UPR. (See page 10, left column bridging right column.) Lie also teaches in a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain, the ER stress and UPR pathways were significantly activated. (See second paragraph of the right column of page 11.)
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
It would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to select the compound 81 of Glimcher out of the list of compounds of the U.S patent claims and use said compound to treat pain to give Applicant’s claimed method. The motivation to do so, is because Glimcher teaches compound 81 as one of the IRE1α inhibitors that can be used to treat the condition that is mediated through the action of IRElα and because Liu teaches taught by Glimcher Pain is caused by the activation of ER stress sensors such as IRE1α and inhibition of said ER stress sensor such as IRE1α can restore pain, and also because Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.). One would reasonably expect the modified compound to successfully treat or reduce pain or inflammatory pain.
With respect to the following limitations:
“the composition reduces prostaglandinendoperoxide synthase 2 (Ptgs2/Cox-2) expression in cells of the subject by a least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%” of claim 11;
“the composition reduces prostaglandin E synthase (Ptges/mPGES-1) expression in cells of the subject by a least 5%” of claim 12;
“the composition does not affect expression of prostaglandin-endoperoxide synthase 1 in cells of the subject” of claim 13;
“the composition does not affect expression of or prostaglandin E synthase 2 in cells of the subject, wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14 and 15;
“the composition reduces concentrations of one or more prostaglandin, arachidonic acid, or a combination thereof in cells of the subject by a least 5%, wherein the prostaglandin is PGE1, 15-keto PGF2a,
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D12-PGJ2 PGD3, PGE2, PGF2a, 13,14dh-15k PGE2, PGD2, PGD3, PGF1ca, or a combination thereof, and wherein the cells are myeloid cells such as dendritic cells, neutrophils, macrophages, or a combination thereof.” of claims 14, 16, and 19;
“the composition reduces concentrations of PGE2 in cells of the subject” of claim 18;
“the pain is reduced in the subject by a least 5%” of claim 20;
“the composition does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 22; and
“the subject does not exhibit side effects selected from stomach pain, heartburn, ulcers, or reduced blood clotting compared to a control subject that did not receive administration of the composition” of claim 23; said limitations are the characteristics or outcome of the method. The claimed characteristics or outcome of the method would flow naturally from the obvious method of the collective teachings of Glimcher and Liu. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant’s argument
Applicant traverses these rejections on the ground that any rejection based on Glimcher and Liu is ineffective in showing the obviousness of the claimed invention for at least the reasons presented in the rejections under section 103. Applicant therefore submits that the claimed invention is not an obvious variation of the claims of US. Patent Nos.i1,125,123 and 10,988,846 in view of Glimcher and Liu. For these reasons, Applicant respectfully requests reconsideration and withdrawal of the double patenting rejections. At a minimum, Applicant requests that the Patent Office hold these rejections in abeyance until the claims of the instant application are held to be allowable.
Examiner’s answer
In response, Applicant’s argument is not persuasive for the same reason outlined in the obviousness rejection section 103 set forth above.
Conclusion
Claims 1-6, 9-20, and 22-27 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628