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 .1
Status of Claims
Claims 1-22 are pending. Claims 11, 12, 14 and 16-21 are under examination.
Election/Restrictions
Claim 1-10, 13, 15 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 16 2022.
Note that claim 15 is withdrawn in addition to claims 1-10, 13 and 22 as it is directed to an ester of a compound formula II, outside the scope of the elected species of formula II, IRX4204.
Applicant’s election without traverse of the below species in the reply filed on March 16 2022 is acknowledged.
Pulmonary fibrosis as a disease species
Thyroxine as a thyroid hormone as a species
IRX42042, i.e. 3,7-dimethyl-6(S),7(S)-methano,7-[1, 1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E), 4(E) heptadienoic acid as a species.
Claim Objections
Claims 11 and 12 are objected to because of the following informalities:
Claim 11 at line 3 is objected to where it recites “the structure,” where it is the first occurrence of the term “structure.” Amendment of claim 11 to recite “a structure” will overcome this objection.
Claim 12 at line 1 is objected to where it recites “wherein is the RXR agonist.” Amendment of claim 12 to delete “is” so that it recites “wherein the RXR agonist” will overcome this objection. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 is only directed to pulmonary fibrosis, depends from claim 11, where claim 11 is also limited to pulmonary fibrosis only. Accordingly, claim 21 fails to further limit claim 11 from which it depends from.
Applicant may cancel claim 21, amend the claim to place it in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11, 12, 14 and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/090616 A1 (WO 616) in view of US Pub 20090227674A1 (US 674) and Tzouvelekis et al. The Immunology of pulmonary fibrosis: The role of Th1/Th2/Th17/Treg cell PNEUMON Number 1, Vol. 23, January - March 2010.
WO 616 and US Pub 767 are cited on IDSs dated May 19 2023 (For Ref No. 7) and (US Pub Ref No. 24). Tzouvelekis is cited on the PTO-892 form.
Claim 11 is directed to a method of treating pulmonary fibrosis, the method comprising administering to an individual in need thereof a therapeutically effective amount of a RXR agonist and a thyroid hormone, wherein the RXR agonist has the structure of Formula II
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wherein R is H or lower alkyl of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof;
wherein administration of the RXR agonist and the thyroid hormone treats the pulmonary fibrosis in the individual more effectively than either the RXR agonist or the thyroid hormone alone.
Note claims 12 and 14 are directed specifically to the species of IRX4204 and thyroxine T4, respectively.
Claim 21 is directed solely to pulmonary fibrosis.
The thyroid hormone (including the species thyroxine, aka T4),
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Regarding claims 11, 12, 14 and 21 and the limitation of the RXR agonist of formula Il (as represented by IRX4204), WO 616 teaches the species IRX4204, see paragraph 59, reproduced below.
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Regarding claims 11, 12, 14 and 21 and the treatment of an autoimmune disease with an RXR agonist, WO '616 teaches the use of RXR agonists to treat autoimmune diseases, see paragraphs 6, 11 and 90-94; see multiple claims, including specifically claims 1-2, 4-5, 15, 26-28 and 33. See paragraphs 11, 90, and 94. More specifically, WO ‘616 teaches its “RXR agonist compounds can control the Th17/Treg cell number by elevating Treg cell numbers and suppressing Th17 cell numbers. As such, the disclosed RXR agonists would be useful in treating an autoimmune disorder.” See paragraph 7.
Although WO '616 teaches the claimed RXR agonist (IRX4204) for treatment of autoimmune disease/conditions (modulated by Th17/Treg cell number), it does not explicitly teach that RXR agonists are administered with thyroid hormones, such as thyroxine, for the treatment of the species of autoimmune related/modulated disease, pulmonary fibrosis.
To address the first issue to combine an RXR agonist with thyroxine, US Pub '674 teaches the necessity of co-administering thyroxine with RXR agonists (bexarotene) because these RXR agonist compounds have a side effect of lowering thyroxine (T4), which is known to be treated by thyroid replacement therapy (thyroxine), see paragraph 285. US Pub '674 teaches the administration of thyroxine (levothyroxine) at a dose 0.05 mg/day in combination with an RXR agonist (bexarotene), see paragraphs 289-292.
To address the treatment of the elected species of pulmonary fibrosis, Tzouvelekis3 teaches pulmonary fibrosis is driven by the Th2 immune response, characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. See page 17 first paragraph.
Similar to the teachings of WO ‘616 regarding Th17 and Treg cells and autoimmune disease, Tzouvelekis teaches two novel CD4 T cell subsets have been demonstrated to play a role with autoimmune pulmonary fibrosis, T helper cell 17 (Th17) and T regulatory cells (Tregs). See page 18, col 1.
Tzouvelekis teaches Tregs suppress activation of the immune system and help maintain immune homeostasis and tolerance to self-antigens. Id. page 18, column 1. The implication of Tzouvelekis is that Treg suppression of immune activation while maintaining immune homeostasis and self-antigen tolerance, will treat a known autoimmune disease such as pulmonary fibrosis.
Similar to limiting fibrosis in lungs, Tzouvelekis teaches Tregs play a pivotal role in limiting collateral damage by suppressing excessive HCV-induced immune activation and limits fibrosis in the liver. See page 19, column 2.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of WO ‘616 to practice the claimed combination of RXR agonist IRX4204 combined with thyroxine (T4) to treat pulmonary fibrosis based on the teachings of US Pub ‘674 and Tzouvelekis (e.g. MPEP 2143 rationale (a), combination of prior art elements according to known methods to yield predictable results).
The PHOSITA would have had a reasonable expectation of success because known RXR agonist IRX4204 is used to treat autoimmune diseases (based on Treg/Th14 effects), where it is known to combine RXR agonists with thyroxine (T4) and the Treg cells regulatory effects are known to treat and control the autoimmune disease pulmonary fibrosis.
With regard to the 4th Graham factor, evidence of unexpected results, Example 3 does point to a greater effect of the combination of IRX4204 and thyroid hormone than each agent individually. However, this result is predictable based on the fact that generally combination treatments are more effective than each individual therapy, at this time and without further evidence, Example 3 fails to provide an unexpected teaching of success/results to overcome the prima facie case. Further, these results are in the context of an EAE model, and not demonstrative of treatment of pulmonary fibrosis.
Similarly, other Examples are directed to non-autoimmune diseases: i.e., Parkinson’s disease Ex. 14-15, a mouse oligodendrocyte cell model with or without Vit. D, Ex. 16-17; Neuroprotective effect of IRX4204 in a mouse model of demyelination, Ex. 18; Rheumatoid Arthritis, Ex. 19; and prophetic examples 20-21 for psoriasis and IBD progression.
Claims 16-17 are directed to where the therapeutically effective amount of the RXR agonist is about 0.001 mg/day to about 1000 mg/day, or is about 1 mg/day to about 100 mg/day.
Regarding claims 16-17, WO ‘616 teaches when administering a compound or a composition disclosed herein to a mammal, a therapeutically effective amount generally is in the range of about 0.001 mg/kg/day to about 100.0 mg/kg/day. In aspects of this embodiment, an effective amount of a compound or a composition disclosed herein can be, e.g., about 0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.03 mg/kg/day to about 3.0 mg/kg/day, about 0.1 mg/kg/day to about 3.0 mg/kg/day, or about 0.3 mg/kg/day to about 3.0 mg/kg/day. In yet other aspects of this embodiment, a therapeutically effective amount of a compound or a composition disclosed herein can be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 10 mg/kg/day, or at least 100 mg/kg/day. In yet other aspects of this embodiment, a therapeutically effective amount of a compound or a composition disclosed herein can be, e.g., at most 0.001 mg/kg/day, at most 0.01 mg/kg/day, at most 0.1 mg/kg/day, at most 1.0 mg/kg/day, at most 10 mg/kg/day, or at most 100 mg/kg/day. See paragraph 111.
Further, WO ‘616 teaches, “[d]osing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art,” see paragraph 113. Accordingly, one of ordinary skill in the art could rely upon the taught doses of WO ‘616 to arrive at the claimed doses of claims 16-17.
Regarding claim 18 where the therapeutically effective amount of the thyroxine is about 12.5 μg/day to about 250 μg/day, US Pub ‘674 teaches the administration of thyroxine (levothyroxine) at a dose 0.05 mg/day (i.e. 50 mcg/day) in combination with an RXR agonist, see paragraphs 289-292.
Claims 19-20 are directed to simultaneous administration and administration on different schedules. US ‘674 teaches concomitant administration with a RXR agonist. See paragraph 89. While not specifically teaching a different schedule of administration, US ‘674 teaches thyroxine therapy should be adjusted as needed. See paragraph 90. As a combination therapy of two medications can be only administered simultaneously or at different schedules, a PHOSITA would routinely optimize dosing to be adjust as need, whether it is done simultaneously or on a different schedule.
Conclusion and Correspondence
In conclusion, no claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a CON of 17/585,349 01/26/2022 PAT 11690832
17/585,349 is a DIV of 17/150,646 01/15/2021 PAT 11690831
17/150,646 is a DIV of 16/083,799 09/10/2018 PAT 10946001
16/083,799 is a 371 of PCT/US2016/059772 10/31/2016
PCT/US2016/059772 has PRO 62/306,479 03/10/2016
2 CAS Registry Number: 220619-73-8 (2E,4E)-3-Methyl-5-[(1S,2S)-2-methyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)cyclopropyl]-2,4-pentadienoic acid (ACI)
(2E,4E)-3-Methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid
AGN 194204
NRX 194204
VTP 194204
3 Tzouvelekis et al. The Immunology of pulmonary fibrosis: The role of Th1/Th2/Th17/Treg cell PNEUMON Number 1, Vol. 23, January - March 2010
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