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 .
Claim Rejections - 35 USC § 112 (Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 5-6, 8-12, 24, 27-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 11 recites “medical condition is fever, a neurodegenerative disease, or pain,” encompassing all neurodegenerative disorders (e.g., Alzheimer’s Parkinson and ALS); Pyrexia from any cause; any pain syndromes (e., g., neuropathic, nociceptive and cancer associated- pain). The specification also fails to provide working examples, models, or data for any of these: fever measurement or reduction, neurodegenerative biomarkers or cognitive tests (e.g., amyloid/tau), and pain behavior test. Rather, the instant claims provide support only for acute viral inflammation in lung/immune cells. The specification provides no guidance on dosing or provide proper models for the claimed conditions, except for influenza A and coronavirus 229E. The specification provides no assessment of patients before and after treatment to show whether the claimed compound is effective at suppressing fever, improve cognitive impairment, and reducing pain. Thus, without such data, a person of ordinary skill in the art (POSITA) would not know whether the compound actually achieves the claim functions.
Claim 28 recites “wherein the citraconic acid or derivative thereof.” The specification (Figure 7) discloses five of the compounds are competitive inhibitors, Ki, with Michaelis-Menten fits; this alone does not establish that they will exhibit the same biological activity. Essentially, shared kinetic profiles do not guarantee comparable in vivo or in vitro activity. Therefore, representative experimental data are still required to enable the full scope of the claimed compound. However, the specification demonstrates disease-relevant cellular efficacy for three of the compounds: citraconic acid, citraconate, and (Z)-2-Ethylbut-2-enedioic. The specification discloses anti-inflammatory, anti-viral, anti-oxidative effects for citraconic acid in influenza A cells (Figure 1-3); (Z)-2-Ethylbut-2-enedioic displays anti-inflammation in LPS-stimulated THP1 cells (Figure 9) and coronavirus-infected endothelial cells (Figure 10); and Citraconate (Figure 7) inhibits production of influenza A progeny virions, but not viral RNA synthesis. Other than Ki values against ACOD1, the specification provides no comparable data for the remaining claimed compounds. The specification has not shown possession of a method of treatment across the claimed genus, relying instead on substantiated extrapolation from enzyme inhibition. Without representative, i.e., lack of in vivo evidence, a POSITA cannot reasonably predict or optimize untested derivatives for dosing, PK/PD, or efficacy, demonstrating a lack of enablement.
Therefore, the lack of enablement of the claimed subject matter at the time of filing, suggest that Applicant did not possess supporting data to claim a method of treating a medical condition administering citraconic acid or derivative.kinase-mediated disease or providing supportive care to a cancer patient.
Written Description
Claim 2 recites “a method for treating a medical condition, comprising administering citraconic acid or derivative thereof according to formula VII to a subject in need thereof.” The formula VII is drawn to a large genuses of compounds (thousands at minimum). The instant claim also recites “a heteroatom” implying multiple alternatives, yet every example uses only an oxygen atom at the R3 and R4 substituents. Thus, the claimed compounds which include only oxygen at R3 and R4 substituents, and either an alkyl or hydrogen at R1 and R2 substituents, does not provide adequate support for the full scope of the claimed genus. It is then recommended that the specification provides support for such a broad claim by providing a representative number of species across the claimed genus.
Regarding a method for treating a medical condition, the instant claim broadly encompassed all medical condition disease, including heart, liver, and Alzheimer's disease, yet the specification's disclosure is clearly limited to influenza A respiratory inflammation, as an example. The specification does not demonstrate possession of treating full genus of any “medical condition” therefore the limited data does not commensurate in scope to support the entire claim. Given a medical condition encompasses a vast of heterogenous group of diseases, each with unique biological characteristic and therapeutic response, thus, it would not be obvious to a person of ordinary skill in the art (POSIT A) to assume that the limited results on influenza A infection in dTHP1/A549 cells and coronavirus 229E in endothelial cells would apply to all medication condition. This further demonstrates that the specification lacks adequate written description of the claimed subject.
Similarly, claims 5 and 8, recites “a disease of the lung” and “chronic inflammation.” The claims broadly encompass all acute inflammatory lung disease (e.g., asthma, COPD cystic fibrosis and bronchitis). The specification, however, provides examples only for influenza A virus (H1N1 PR8N) infection in A549 lung epithelial cells, reducing progeny virions (Figure 7). While certain, but not all, antiviral drugs (e.g., Baloxavir) used for influenza A also work against influenza B, C, and D. However, the specification fails to indicate whether the claimed compounds are also effective against influenza variant B, C, and D. Furthermore, the claim breadth far exceeds the single example of acute viral model, this is because influenza is an acute viral respiratory infection and is considered an acute inflammatory illness and not chronic. This further demonstrates that the specification lacks adequate written description of the claimed subject, chronic inflammation and any lung infection.
Claim 9 recites “a viral infection.” The claims broadly encompass any viral infection (e.g., coronaviruses, RSV, HIV, herpes, and rhinoviruses). The specification presents only two specific acute respiratory RNA viruses: influenza A viruses and human coronavirus 229E (Figure 1-3, 7 and 10), which represent a small subset of the broad genus recited in the instant claim. The instant claim evidence is based on host-directed modulation of inflammation pathways (e.g., ACOD1 inhibition, Nrf2, as an example), which are not uniform across all viruses; because such pathway varying significantly based on the virus type, the host cell, and the stage of infection. It would not be obvious to a person of ordinary skill in the art (POSITA) to assume that influenza A and human coronavirus 229E herein, would apply to all types of viruses or viral infection. Thus, the limited disclosure does not provide adequate support for the full scope of the claimed genus. This further demonstrates that the specification lacks adequate written description of the claimed subject.
Claim 24 recites “wherein the viral infection is an influenza virus, zika virus or coronavirus infection.” The claims broadly encompass any viral infection influenza virus, zika virus or coronavirus infection. The specification, however, provides examples only for influenza A virus (H1N1 PR8N) infection in A549 lung epithelial cells, and human coronavirus 229E in endothelial cells (Figure 7). Regarding zika virus, the specification contains no data, experiments, models, discussion, or rational linking citraconic or derivative to zika infection. The specification does not demonstrate possession of full genus of any “any viral infection” therefore the limited data on influenza A virus, and human coronavirus 229E do not commensurate in scope to support the entire claim. This further demonstrates that the specification lacks adequate written description of the claimed subject.
Claims 29, 31, 33-34, and 36-37 recites “medical condition is cancer.” The claims broadly encompass any cancer. The prediction is mainly based on ACOD1 overexpression and activity (specification page 11, line 13-15):
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The specification, however, fails to disclose any data, and working examples showing that the claimed compounds treat cancer. The specification (page 6, lines 32-36) further underscores this deficiency, due to the presumptive or prophetic statement without supporting evidence:
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Furthermore, the lack of any approved drug acting as ACOD-1inhibitor, further indicate that robust data are needed to support the asserted therapeutic effect across any cancer.
The specification’s failures to disclose a proper representative number of species across the claimed genus, thereof supports the conclusion that the specification lacks adequate written description of the claimed subject matter. Thus, a POSITA would conclude that Applicant was not in possession of the entirety of the claimed genus at the time of filling of the instant application in view of the disclosure of the application as filed.
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 6 are rejected under 35 U.S.C. 102(a)(l) as being anticipated by
Chien et al., J Agric Food Chem. 2008 Aug 27;56(16):7017-22.
Regarding claims 2 and 6, Chien (abstract; page 7019) discloses a compound 6, dimethyl 2-(4-hydroxyphenyl)-3-isobutylmaleate, with anti-inflammatory property by suppressing IL-6 production in LPS stimulated macrophages. Compound 6 clearly meets each and every chemical variable as listed in the instant claim, wherein R3 and R4 = O; R1 and R2 = CH3; R5 = phenyl substituted with hydroxy; R6 = isobutyl.
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Chien (abstract; page 7020-7021, Table 3-4) teaches compound 6 with therapeutic for treating medical condition associated with inflammation. Given that LPS-stimulated macrophages, such condition anticipates to be an acute inflammation, leading to production of pro-inflammatory cytokines such as TNF-α, and IL-6.
Therefore, claims 2 and 6 are anticipated.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5, 8-12, 24, 27 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Chien, as applied to claims 2 and 6 in view of Shimura et al. US 2007/0248705A1.
Chien (abstract; page 7019), as applied to claims 2 and 6 above, discloses a compound 6, dimethyl 2-(4-hydroxyphenyl)-3-isobutylmaleate, possessing anti-inflammatory property.
Chien, however, does not explicitly teach the various disease state recited in the instant claim.
Shimura (abstract; page 1, [0003]; page 6, [0066] and [0067]) teaches activation of transcription factors or Nrf2 and methods of using Nrf2-activating compounds to treat inflammatory and oxidative stress-related disease, including but not limited to chronic inflammatory disease and cancer. It is important to highlight that the specification (page 6, line 15-18, page 30 and 32) teaches citraconic acid, a compound of formula VII, as an Nrf2 activator. Given that Chien teaches compounds that structurally encompassed by the instant claim, thus, a person of ordinary skill in the art (POSITA) would have reasonably expected the compounds disclosed by Chien to exhibit similar biological activity as citraconic acid, including activation of the Nrf2 signaling pathway. Consequently, it would have also been obvious to a POSITA to combine the teachings of Chien and Shimura to arrive at the claimed invention, since Shimura teaches the use of Nrf2-activating compound to treat or prevent disease, including but not limited to inflammatory disorder (e.g., rheumatoid arthritis) and cancer.
Subject Matter Free of the Art of Record
The subject matter of claims 28, 30-37 are free of the art of record. The closest prior art is the Chien et al., J Agric Food Chem. 2008 Aug 27;56(16):7017-22. While Chien teaches a compound 6, dimethyl 2-(4-hydroxyphenyl)-3-isobutylmaleate, with anti-inflammatory property. However, there is no motivation for a POSITA to modify the teachings of Chien to arrive at the claimed compound. These claims are not allowable until the 112 is resolved or overcome.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622