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 .
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
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on July 24, 2026. 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 Claims 7 and 8 are withdrawn.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
Upon consideration of the record and Applicant’s argument submitted on 07/24/2026, the rejection of claims 1-6 and 9-27 based on improper Markush grouping of alternatives is withdrawn. The withdrawal of the rejection is based upon reconsideration of the rejection as presently articulated and should not be construed as affirmative determination that all alternatives encompassed by the presently claimed Markush group satisfy the requirement for a proper Markush grouping under in re Harnisch and MPEP § 2117.
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), 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), are revised because the reason revision is necessitated by Applicant’s newly added “sole therapeutic agent” limitation.
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), 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), are modified and revisited in light of the amendment to claim 1. This rejection is directed to claim 21 which depends from claim 1 and is therefore incorporates all limitations of amended claim 1, including the newly added requirement concerning the claimed compound being the sole therapeutic agent administered for reducing pain. The record is clarified to include claim 21 in the header of the rejection.
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 revised because the reason revision is necessitated by Applicant’s newly added “sole therapeutic agent” limitation.
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 revised because the reason revision is necessitated by Applicant’s newly added “sole therapeutic agent” limitation.
New Rejection necessities by claim amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6 and 9-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 1 recites, in pertinent part, administering a composition comprising “one or more compounds” of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and further recites that “the one of more compounds of formula I or formula II, or a pharmaceutically acceptable salt thereof, is the sole therapeutic agent administered for reducing the pain in the subject.”
Independent claim 27 likewise recites, in pertinent part, administering a composition comprising “one or more compounds” of any of Tables 1-7, or a pharmaceutically acceptable salt thereof, and further recites that “the one of more compounds of any of Tables 1-7, or a pharmaceutically acceptable salt thereof, is the sole therapeutic agent administered for reducing the pain in the subject.”
The scope of claims 1 and 27 is unclear because each claim expressly permits administration of more than one compound, while simultaneously requiring “the one or more compounds” to be “the sole therapeutic agent” administered for reducing pain. When more than one of the recited compounds is administered, it is unclear whether (i) the plurality of compounds collectively constitutes a single “therapeutic agent” for purposes of the “sole therapeutic agent” limitation, or (ii) each administered compound constitutes a separate therapeutic agent, in which case administration of two or more such compounds, appear inconsistent with the requirement that the compound be the sole therapeutic agent administered for reducing pain.
Thus, the claimed language is susceptible to more than one reasonable interpretation and does not clearly establish whether the claims encompass administration of multiple claimed compounds for reducing pain or instead require administration of only a single claimed compound for reducing pain. Accordingly, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed subject matter. For examination, purpose, and without waiving the foregoing rejection, claims 1 and 27 are interpreted under the broadest reasonable interpretation as encompassing administration of one or more of the recited compounds, including an embodiment in which a single recited compound is administered as the sole therapeutic agent for reducing pain.
Claim 27 further recites “administering a composition comprising one or more compounds of any of Tables 1-7 or a pharmaceutically acceptable salt thereof.” The claim therefore defines compounds required by the claimed method through incorporation by reference to Tables 1-7 of the specification rather than defining the compounds within the claim itself.
Claims are to be complete in themselves where possible. Incorporation by reference to a specific figure or table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where incorporation by reference is more concise than reproducing the relevant drawing or table into the claim. See MPEP § 2173.05(s); Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
In the present case, Applicant has not established exceptional circumstances demonstrating that there is no practical manner of defining the claimed compounds within the claim. Rather, claim 27 requires reference to seven separate tables in the specification to ascertain which chemical compounds constitute the recited “one of more compounds.” Accordingly, the claim is not complete in itself and fails to particularly point out and distinctly define the scope of the claimed subject matter.
Modified and Revised Rejection necessitated by claim amendment
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).
The teachings and findings of the references set forth in the previous Office action are maintained except to the extent expressly modified herein in view of Applicant’s amendments.
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].)
In summary, Glimcher teaches compounds that inhibit IRE1α and pharmaceutical compositions containing such compounds. Glimcher also teaches that administration of the disclosed compounds for treatment, prevention, elimination, alleviation, or amelioration of diseases or conditions mediated through IRE1α, including inflammatory conditions. Of particular relevance, Glimcher expressly discloses Compound 81, which is the elected compound presently under examination. Thus, the rejection is not selecting an unidentified species from an unidentified genus Rather, Compound 81 is an expressly disclosed and exemplified compound of Glimcher having the disclosed IRE1α inhibitory activity.
Glimcher, however, does not expressly teach Compound 81 for the presently claimed purpose of reducing pain in a subject as the sole active agent.
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.)
In Sum, Liu teaches that endoplasmic-reticulum stress and the unfolded-protein response are implicated in chronic pain states, including inflammatory and neuropathic pain. Liu identifies the IRE1/XBP1 pathway as one of the principal ER-stress/unfolded-protein-response signaling pathways and reports that involvement of ER-stress signaling in pai-associated biological response. Liu therefore, provides evidence known in the art that the biological pathway inhibited by Glimcher’s compounds, including IRE1α signaling is relevant to pain.
The Office does not rely upon Liu for the proposition that Lie expressly administers Glimcher Compound 81 as a stand-alone analgesic. Nor is the present rejection premised upon removing morphine from Liu’s experimental method. Rather, Liu is relied upon for what its disclosure would have taught one of ordinary skill concerning the relationship between ER-stress/UPR signaling, including IRE1-associated signaling and pain.
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
In sum, Omoigui teaches that pain is associated with inflammatory processes and describes the relationship between inflammation and the generation and maintenance of pain. Omoigui therefore provides additional evidence that modulation of an inflammatory pathway would have been reasonably investigated as a means of reducing pain.
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.)
Gui and Lin are maintained for the teachings for which they were previously relied upon, including the relationship between ER-stress signaling pathways and pain, hyperalgesia, allodynia, and related nociceptive responses. In particular, these references further support the art-recognized relationship between ER-stress/IRE1-associated signaling and pain-related biological responses and therefore reinforce the reason one of ordinary skill would have had to investigate inhibition of the pathway for reducing pain.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to employ Glimcher’s expressly disclosed Compound 81 for reducing pain.One would have been motivated to do so because Glimcher teaches Compound 81 as an IRE1α inhibitor and teaches therapeutic administration of its IRE1α inhibitor for conditions mediated through IRE1α, including inflammation, whereas Liu, Omoigui, Qui, and Lin collectively teach that ER-stress/UPR and inflammatory signaling are associated with pain, including inflammatory and/or neuropathic pain and related nociceptive responses. Thus, the cited references would have provided one of ordinary skill with a reason to employ a known inhibitor of IRE1α-specifically Glimcher’s expressly disclosed Compound 81-to modulate a pathway recognized in the art as being associated with pain.
The proposed modification does not require bodily incorporation of the experimental procedure of Liu, Gui, Lin, or Omoigui into Glimcher. Rather, those references provide knowledge concerning the biological relationship between the molecular pathway inhibited by Glimcher’s Compound 81 and pain and thereby provide the reason for employing Compound 81 for the claimed therapeutic purpose.
One of ordinary skill in the art would also have had a reasonable expectation of success. Glimcher establishes that Compound 81 is an IRE1α inhibitor. The secondary reference establishes that ER-stress/UPR and inflammatory signaling, including signaling involving the IRE1 pathway, are implicated in pain-related states. Accordingly, one of ordinary skill reasonably have expected that inhibition of the implicated pathway by a known IRE1α inhibitor would provide a therapeutic benefit in reducing pain. Obviousness does not require absolute predictability or a guarantee that the treatment will achieve a particular magnitude or response in every subject. The collective teachings need only provide a reasonable expectation that the proposed therapeutic use would succeed.
Newly added “sole therapeutic” limitation. Applicant has amended to the claim to require, in substance, that the recited compound or compounds to be “sole therapeutic agent administered for reducing pain.” The amendment does not overcome the rejection because the Office’s obviousness rationale does not require administration of morphine or another therapeutic agent for reducing pain. As previously set forth, the rejection included the alternative rationale of employing Compound 81 itself for pain or inflammatory pain. The morphine-related teaching constituted an additional or alternative aspect of the analysis and were not indispensable to the conclusion that one of ordinary skill would have had reason to employ Compound 81 itself for reducing pain. The presently maintained modification is therefore to administer Compound 81 itself for reducing pain based upon its known IRE1α inhibitory activity and the prior-art recognition of the relationship between ER-stress/IRE1/inflammatory signaling and pain.
Accordingly, the newly added limitation requiring the claimed compound to be the sole therapeutic agent administered for reducing pain does not distinguish the claimed method from the method that would have been obvious from the combined teachings of the cited references.
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).
Modified and Revised Rejection necessitated by claim amendment
Claim 21 is 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, motivation to combine, and the reasonable expectation of success set forth in the rejection of claim 1 above are incorporated herein.
The primary combination does not expressly teach the additional pain-assessment limitation of claim 21.
Glimcher, Liu, Omoigui, Gui, and Lin collectively do not teach the pain is measured by the subject's number of writhing’s 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 as recited in claim 21. Claim 21, however, recites the claimed measurements in the alternatives, using “or.” Thus, the prior art needs to not establish every recited measurement. A teaching of or suggestion rendering obvious at least one of the alternatives recited manners of assessing pain is sufficient to meet the alternative limitation.
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. Pavlin reports that increasing maximum pain scores were associated with increasing total recovery time, reporting recovery times of approximately 135, 172, and 212 minutes for the respective maximum-pain-score categories reported in this study (See Abstract.)
Pavlin therefore establishes that, in ambulatory surgical subjects, pain was quantitatively evaluated in relation to a measured temporal recovery parameter.
One of ordinary skill in the art at seeking to determine whether administration of the pain-reducing treatment rendered obvious by Glimcher and the secondary references was effective would have had reason to employ an objective or quantitative assessment of the subject’s behavior or recovery over a selected period of time. Pavlin provides evidence that temporal and ambulatory-recovery parameters were recognized measures associated with the evaluation of postoperative pain and recovery. Accordingly, it would have been obvious to monitor an ambulatory/time-dependent parameter in determining the effectiveness of the pain-reducing treatment.
The motivation would have been to provide an objective and reproducible measure by which the effectiveness of the therapeutic intervention could be evaluated rather than relying exclusively upon a subjective report of pain.
One or ordinary skill in the art would have a reasonable expectation of success because Pavlin demonstrates the feasibility of quantitatively assessing pain and recovery in ambulatory subjects over measured period of time.
The newly added “Sole therapeutic agent” limitation does not alter this conclusion because that limitation is inherited from claim 1 and is addressed by the principal combination as explained in the first obviousness rejection above. Pavlin is relied upon for the additional pain-assessment subject matter of claim 21, not for the identity or number of therapeutic agents administered.
Applicant’s argument
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on July 24, 2026. Applicant’s arguments have been full considered but are not persuasive.
Applicant argues that the rejection is overcome because Liu administers an IRE1α-
directed intervention in connection with morphine and therefore allegedly fails to teach or suggest administration of the claimed compound as the sole therapeutic agent for reducing pain.
In response, this argument is not persuasive. This argument does not address the rejection as a whole. The rejection was not dependent exclusively upon coadministration of Compound 81 and morphine. The previous rejection expressly presented an alternative rationale directed to employing Compound 81 for pain or inflammatory pain, in addition to the alternative discussion involving morphine. The modified rejection does not require morphine. Specifically, Glimcher teaches Compound 81 as an IRE1α inhibitor. Liu, Gui, and Lin provide teachings concerning the involvement of ER-stress/UPR signaling, including IRE1-associated signaling, in pain-related states. Omoigui further teaches the relationship between inflammatory processes and pain. Accordingly, the collective teachings would have provided on of ordinary skill with reason to administer Compound 81 itself for reducing pain and inflammatory pain.
Applicant’s amendment specifying that the claimed compound is the sole therapeutic agent administered for reducing pain therefore does not overcome the rejection.
Applicant agues that Liu does not establish that inhibition of IRE1α, standing alone,
produces analgesia. The Office agrees Liu need not be interpreted as expressly demonstrating that Glimcher Compound 81 independently functions as an analgesic. Such an express disclosure is not necessary to the rejection. Liu is relied upon for its teaching concerning the biological relationship between ER stress/UPR signaling and pain. That teaching is considered together with Glimcher’s teaching of Compound 81 as an inhibitor of IRE1α. The obviousness inquiry concerns what the references collectively would have suggested to one of ordinary skill, rather than whether Liu along expressly describes the complete claimed method.
Applicant’s reliance upon the principle that a proposed modification should not
render a prior-art-reference unsatisfactory for its intended purpose is not persuasive. The Office is not proposing that morphine be removed from Liu’s experimental protocol while expecting Liu’s protocol to continue performing its intended purpose. Rather, Liu is relied upon as evidence of what was known concerning the relationship between ER-stress/IRE1 signaling and pain. That knowledge provides a reason for employing Glimcher’s IRE1α’s inhibitor Compound 81 for reducing pain. Thus, the proposed modification is directed to Glimcher’s therapeutic method, informed by the biological teachings of the secondary references. It does not require alteration of Liu in a manner that destroys Liu’s intended operation.
Accordingly, Applicant’s argument does not address the actual rationale of the rejection.
Applicant’s argument that the Office lacks a reason for selecting the present
claimed compound is not persuasive. Compound 81 is not reconstructed from disconnected substituent selections made with knowledge of Applicant’s disclosure. Glimcher expressly discloses Compound 81. Moreover, Compound 81 is the elected species presently under examination. Thus, the Office’s selection of Compound 81 is grounded directly in Glimcher’s express disclosure and known IRE1α inhibitory activity rather than hindsight reconstruction.
Applicant argues that the references fail to provide a reason to administer
Compound 81 for reducing pain.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, Glimcher provides the compound and its IRE1α inhibitory activity, Liu, Qui, and Lin provide the relationship between ER-stress/IRE1-asscociated signaling and pain-related biological states. Omoigui provides additional teaching concerning the relationship between inflammation and pain.
A person of ordinary skill is presumed to possess the knowledge of the prior art as a whole. Considered collectively, the references provided a reason to employ the known IRE1α inhibitor for a condition associated with the inhibited signaling pathway.
Applicant further argues that there would have been no reasonable expectation of
that Compound 81 alone would reduce pain.
In response, this argument is not persuasive. The standard is reasonable expectation of success, not absolute predictability or certainty. Glimcher teaches that Compound 81 inhibits IRE1α, while the secondary references establish that ER-stress/UPR and inflammatory signaling are implicated in pain. Those teachings would have provided one of ordinary skill with a reasonable scientific basis for expecting inhibition of the implicated pathway to provide a therapeutic benefit in reducing pain.
To the extent Applicant argues that Pavlin does not teach every measurement
recited in claim 21, the argument is not commensurate with the scope of the claim. Claim 21 recites the respective measurements using “or.” Therefore, the alternatives are not cumulative requirements. Pavlin provides evidence of quantitative evaluation of pain and recovery in ambulatory surgical patients and demonstrates a relationship between pain severity and measured recovery time. When considered with the principal combination, Pavlin would have provided a reason to employ an objective temporal/ambulatory measure for evaluating the effectiveness of the pain-reducing treatment.
Modified and Revised Rejection necessitated by claim amendment
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 are 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 as the sole active therapeutic agent for reducing pain.
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.)
In Sum, Liu teaches that endoplasmic-reticulum stress and the unfolded-protein response are implicated in chronic pain states, including inflammatory and neuropathic pain. Liu identifies the IRE1/XBP1 pathway as one of the principal ER-stress/unfolded-protein-response signaling pathways and reports that involvement of ER-stress signaling in pai-associated biological response. Liu therefore, provides evidence known in the art that the biological pathway inhibited by Glimcher’s compounds, including IRE1α signaling is relevant to pain.
The Office does not rely upon Liu for the proposition that Lie expressly administers Glimcher Compound 81 as a stand-alone analgesic. Nor is the present rejection premised upon removing morphine from Liu’s experimental method. Rather, Liu is relied upon for what its disclosure would have taught one of ordinary skill concerning the relationship between ER-stress/UPR signaling, including IRE1-associated signaling and pain.
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
In sum, Omoigui teaches that pain is associated with inflammatory processes and describes the relationship between inflammation and the generation and maintenance of pain. Omoigui therefore provides additional evidence that modulation of an inflammatory pathway would have been reasonably investigated as a means of reducing pain.
It would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to modify the subject matter encompassed by the U.S. patent claims be selecting and employing Compound 81 of Glimcher, which reads on the elected compound, for reducing pain in a subject. The motivation to do so would have arisen from the structural and functional relationship between the compounds encompassed by the U.S. patent claims and Compound 81 expressly exemplified by Glimcher, considered together with the known biological relationship between IRE1α/ER-stress signaling and pain. Specifically, the U.S. patent claims encompass the recited Formula Ia structural class but do not specifically recite the elected compound. Glimcher expressly exemplifies Compound 81 as a preferred compound of Formula Ia (Table 4. P. 25), and Compound 81 reads on the elected compound. Glimcher further identifies its Compounds, including Compound 81, as IRE1α inhibitors and teaches their therapeutic administration for conditions mediated through IRE1α, including inflammation (Abstract; ¶ [0172]). Thus, Glimcher does not merely provide an arbitrary compound selected from an unrelated chemical class. Rather, Glimcher provides an expressly IRE1α-inhibiting compound within the relevant structural class that supplies the elected compound species not specifically recited in U.S. patent claims. One of ordinary skill therefore would have had reason to select Compound 81 as a suitable species for therapeutic use based upon its expressly disclosed IRE1α inhibitory activity.
Liu further teaches that endoplasmic-reticulum stress and the unfolded-protein response are implicated in chronic pain states, including inflammatory and neuropathic pain, and identifies IRE1/XBP1 as one of the principal ER-stress/UPR signaling pathways. Liu further reports activation of ER-sress and UPR pathways in an L5 spinal nerve ligation model of neuropathic pain (p. 11, right column, second ¶). Accordingly, Liu provides evidence that the biological pathway inhibited by Glimcher’s compounds, including IRE1α-associated signaling, is relevant to pain.
Omoigui additionally teaches that pain is associated with inflammation and the inflammatory response (Title; Abstract), whereby providing further reason toe employ an inhibitor taught for an IRE1α-mediated inflammatory condition in a method directed for reducing pain.
Accordingly, one of ordinary skill in the art, having the compounds encompassed by the U.S. patent claims and seeking a therapeutically useful species for reducing pain, would have had reason to select the structurally related and expressly exemplified Compound 81 of Glimcher because Compound 81 is identified as an IRE1α inhibitor; Glimcher teaches therapeutic use of such inhibitors for IRE1α-mediated conditions, including inflammation; Liu teaches that ER-stress/UPR signaling, including IRE1-associated signaling, is implicated in chronic inflammatory and neuropathic states; and Omoigui independently teaches the relationship between inflammation and pain. The collective teachings therefore would have provided a reason, based upon the known structural and functional properties of Compound 81 and the known biological mechanism associated with pain, to employ Compound 81 for reducing pain.
One of ordinary skill in the art would have had a reasonable expectation of success in using Compound 81 to reduce pain. Glimcher expressly establishes that Compound 81 is an IRE1α inhibitor and teaches the therapeutic administration of its IRE1α inhibitors for conditions mediated through IRE1α, including inflammation. Liu establishes that ER-stress/UPR signaling is activated in chronic pain states and identifies IRE1 as one of the ER-stress sensors involved in that signaling, while Omoigui teaches the relationship between inflammatory processes and pain. Taken together, these teachings would have provided a reasonable scientific basis for expecting that administration of a known IRE1α inhibitor, such as Compound 81, would beneficially modulate an IRE1α/ER-stress-associated inflammatory pathway implicated in pain and thereby reduce pain. Absolute predictability is not required. Rather, the collective teachings would have provided one of ordinary skill with a reasonable expectation that the proposed use would achieve the intended pain-reducing result.
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).
The Examiner notes that the proposed modification does not require removal of morphine from Liu’s experimental model, nor does it depend upon coadministration of morphine with Compound 81. Liu is relied upon for what it teaches one of ordinary skill regarding the relationship between ER-stress/UPR signaling, including IRE1-associated signaling and pain. The therapeutic Compound supplied by the modification of Compound 81 of Glimcher.
Accordingly, the amendment requires the claimed compound be the “sole therapeutic agent administered for reducing the pain” does not render the claimed subject matter patentably distinct. The proposed modification is to employ Compound 81 itself for reducing pain based upon IRE1α inhibitory activity and the prior-art relationship between IREα/ER-stress/inflammatory signaling and pain. The rationale therefore does not require administration of morphine or another therapeutic agent for reducing pain.
To the extent the previous rejection additionally contemplated an embodiment involving a subject receiving morphine for pain, the presently amended limitation may exclude that particular alternative where morphine constitutes another therapeutic agent administered for reducing the same pain. However, the rejection did not depend exclusively upon that alternative. The separately articulated basis for employing Compound 81 itself to treat or reduce pain or inflammatory pain remains applicable to the presently amended claims.
Therefore, the presently claimed method, including administration of the elected Compound 81 as the sole therapeutic agent administered for reducing pain, would have been an obvious variation of the subject matter encompassed by the U.S. patent claims.
Claims 1-6, 9-20, and 22-27 are 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 as the sole therapeutic agent for reducing pain.
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.)
In Sum, Liu teaches that endoplasmic-reticulum stress and the unfolded-protein response are implicated in chronic pain states, including inflammatory and neuropathic pain. Liu identifies the IRE1/XBP1 pathway as one of the principal ER-stress/unfolded-protein-response signaling pathways and reports that involvement of ER-stress signaling in pai-associated biological response. Liu therefore, provides evidence known in the art that the biological pathway inhibited by Glimcher’s compounds, including IRE1α signaling is relevant to pain.
The Office does not rely upon Liu for the proposition that Lie expressly administers Glimcher Compound 81 as a stand-alone analgesic. Nor is the present rejection premised upon removing morphine from Liu’s experimental method. Rather, Liu is relied upon for what its disclosure would have taught one of ordinary skill concerning the relationship between ER-stress/UPR signaling, including IRE1-associated signaling and pain.
Omoigui teaches the biochemical origin of all pain is inflammation and the inflammatory response. (See Title and Abstract.)
In sum, Omoigui teaches that pain is associated with inflammatory processes and describes the relationship between inflammation and the generation and maintenance of pain. Omoigui therefore provides additional evidence that modulation of an inflammatory pathway would have been reasonably investigated as a means of reducing pain.
It would have been prima facie obvious to one ordinary skill in the art at the time the invention was filed to modify the subject matter encompassed by the U.S. patent claims be selecting and employing Compound 81 of Glimcher, which reads on the elected compound, for reducing pain in a subject. The motivation to do so would have arisen from the structural and functional relationship between the compounds encompassed by the U.S. patent claims and Compound 81 expressly exemplified by Glimcher, considered together with the known biological relationship between IRE1α/ER-stress signaling and pain. Specifically, the U.S. patent claims encompass the recited Formula Ia structural class but do not specifically recite the elected compound. Glimcher expressly exemplifies Compound 81 as a preferred compound of Formula Ia (Table 4. P. 25), and Compound 81 reads on the elected compound. Glimcher further identifies its Compounds, including Compound 81, as IRE1α inhibitors and teaches their therapeutic administration for conditions mediated through IRE1α, including inflammation (Abstract; ¶ [0172]). Thus, Glimcher does not merely provide an arbitrary compound selected from an unrelated chemical class. Rather, Glimcher provides an expressly IRE1α-inhibiting compound within the relevant structural class that supplies the elected compound species not specifically recited in U.S. patent claims. One of ordinary skill therefore would have had reason to select Compound 81 as a suitable species for therapeutic use based upon its expressly disclosed IRE1α inhibitory activity.
Liu further teaches that endoplasmic-reticulum stress and the unfolded-protein response are implicated in chronic pain states, including inflammatory and neuropathic pain, and identifies IRE1/XBP1 as one of the principal ER-stress/UPR signaling pathways. Liu further reports activation of ER-sress and UPR pathways in an L5 spinal nerve ligation model of neuropathic pain (p. 11, right column, second ¶). Accordingly, Liu provides evidence that the biological pathway inhibited by Glimcher’s compounds, including IRE1α-associated signaling, is relevant to pain.
Omoigui additionally teaches that pain is associated with inflammation and the inflammatory response (Title; Abstract), whereby providing further reason toe employ an inhibitor taught for an IRE1α-mediated inflammatory condition in a method directed for reducing pain.
Accordingly, one of ordinary skill in the art, having the compounds encompassed by the U.S. patent claims and seeking a therapeutically useful species for reducing pain, would have had reason to select the structurally related and expressly exemplified Compound 81 of Glimcher because Compound 81 is identified as an IRE1α inhibitor; Glimcher teaches therapeutic use of such inhibitors for IRE1α-mediated conditions, including inflammation; Liu teaches that ER-stress/UPR signaling, including IRE1-associated signaling, is implicated in chronic inflammatory and neuropathic states; and Omoigui independently teaches the relationship between inflammation and pain. The collective teachings therefore would have provided a reason, based upon the known structural and functional properties of Compound 81 and the known biological mechanism associated with pain, to employ Compound 81 for reducing pain.
One of ordinary skill in the art would have had a reasonable expectation of success in using Compound 81 to reduce pain. Glimcher expressly establishes that Compound 81 is an IRE1α inhibitor and teaches the therapeutic administration of its IRE1α inhibitors for conditions mediated through IRE1α, including inflammation. Liu establishes that ER-stress/UPR signaling is activated in chronic pain states and identifies IRE1 as one of the ER-stress sensors involved in that signaling, while Omoigui teaches the relationship between inflammatory processes and pain. Taken together, these teachings would have provided a reasonable scientific basis for expecting that administration of a known IRE1α inhibitor, such as Compound 81, would beneficially modulate an IRE1α/ER-stress-associated inflammatory pathway implicated in pain and thereby reduce pain. Absolute predictability is not required. Rather, the collective teachings would have provided one of ordinary skill with a reasonable expectation that the proposed use would achieve the intended pain-reducing result.
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).
The Examiner notes that the proposed modification does not require removal of morphine from Liu’s experimental model, nor does it depend upon coadministration of morphine with Compound 81. Liu is relied upon for what it teaches one of ordinary skill regarding the relationship between ER-stress/UPR signaling, including IRE1-associated signaling and pain. The therapeutic Compound supplied by the modification of Compound 81 of Glimcher.
Accordingly, the amendment requires the claimed compound be the “sole therapeutic agent administered for reducing the pain” does not render the claimed subject matter patentably distinct. The proposed modification is to employ Compound 81 itself for reducing pain based upon IRE1α inhibitory activity and the prior-art relationship between IREα/ER-stress/inflammatory signaling and pain. The rationale therefore does not require administration of morphine or another therapeutic agent for reducing pain.
To the extent the previous rejection additionally contemplated an embodiment involving a subject receiving morphine for pain, the presently amended limitation may exclude that particular alternative where morphine constitutes another therapeutic agent administered for reducing the same pain. However, the rejection did not depend exclusively upon that alternative. The separately articulated basis for employing Compound 81 itself to treat or reduce pain or inflammatory pain remains applicable to the presently amended claims.
Therefore, the presently claimed method, including administration of the elected Compound 81 as the sole therapeutic agent administered for reducing pain, would have been an obvious variation of the subject matter encompassed by the U.S. patent claims.
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 arguments are not persuasive for the same reason outlined in the obviousness rejection section 103 set forth above.
Applicant’s request that the nonstatutory double patenting rejection be held in abeyance until the pending claims are otherwise determined to be allowable has been considered but is not persuasive. The presently pending claims remain subject to the respective nonstatutory double patenting rejections. Accordingly, there is no reason on the present recor to defer consideration of these rejections merely because other grounds of rejection remain outstanding.
Conclusion
Claims 1-6 and 9-27 are not allowed.
THIS ACTION IS MADE FINAL. 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.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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