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 .
Status of the Application
Applicant's election without traverse of the species, cytokine release syndrome (CRS) and compound 1, in the reply filed 12/18/25 is acknowledged.
Claims 1-3, 9, 13, 16, 27-28, 32, 34, 37, 39, 41, 50, 53-55, 57-58, 70, 133 are pending. Claims 2-3, 9, 13, 16, 27, 32, 37, 39, 41, 50, 53-54, 57-58, 70 have been amended. Claims 13, 16, 133 have been withdrawn from further consideration as being drawn to a non-elected species. Claims 1-3, 9, 27-28, 32, 34, 37, 39, 41, 50, 53-55, 57-58, 70 are examined herein insofar as they read on the elected invention and species.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham vs John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-3, 9, 27-28, 32, 34, 37, 39, 41, 50, 53-55, 57-58, 70 are rejected under 35 U.S.C. 103(a) as being obvious over Nguyen et al. (US Patent 10,653,669, of record) in view of Gill et al. (WO 2018/013918).
The instant claims are directed to a method of treating a patient who has, or who is at risk for developing, systemic immune activation by administering a compound of formula I, wherein the systemic immune activation is cytokine release syndrome (CRS).
Nguyen et al. teach that microglia in older mice exhibit an inflammatory phenotype, evidenced by a significant increase in CCL2 and TNF-α production. Tumor necrosis factor (TNF or TNF-α) is a cell signaling protein (cytokine) that make up an acute phase reaction. The chemokine (C-C motif) ligand 2 (CCL2) is a small cytokine, which recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection. By administering ZLN005 (same structure as instant compound 1) to older animals, CCL2 and TNF-α production in microglia decreased. In addition, ZLN005 treatment suppressed systemic inflammation in older mice as evidenced by its inhibitory effect on serum TNF-α levels (col. 3, lines 7-21). Dosage forms include tablets, capsules, powders, or solutions (col. 3, lines 40-48) and can be administered intravenously or orally (col. 5, lines 18-26). The dosage amount can be from 1-25, preferably 0.3-20, and more preferably 0.3-3 mg/kg/day (col. 5, lines 32-38).
However, Nguyen et al. fail to disclose CRS.
Gill et al. teach that CRS is a severe form of systemic inflammation with massive release of cytokines, such as IFNg, TNF-α, IL-6, and others, representing a systemic inflammatory state and can lead to serious toxicities including death. CRS is characterized by high fevers and a systemic inflammatory response that may progress to hypotension, hypoxia, altered mental status, multi-organ dysfunction and death (page 410, first full paragraph). The method also includes the step of determining the level of C-reactive protein (CRP) in the subject with a high risk of severe CRS having a level greater than 7 mg/dL (page 45, lines 27-30). Similarly, the same subject will have elevated IL-6 values relative to a reference (page 45, lines 4-26).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time the claimed invention was made, to have administered ZLN005, as taught by Nguyen et al., to treat a subject with CRS, as taught by Gill et al.
A person of ordinary skill in the art would have been motivated to administer ZLN005 to treat CRS because Nguyen et al. clearly teaches that ZLN005 is useful for treating systemic inflammation, which is characterized by increased levels of cytokines, for example TNF-α. Furthermore, Gill et al. clearly teaches that CRS is a severe form of systemic inflammation with elevated levels of cytokines, such as IFNg, TNF-α, and IL-6. Therefore, the skilled artisan would have had a reasonable expectation of success in treating CRS because the same systemic inflammation that can be treated by ZLN005 can also be effectively used to treat CRS since the disease is a known form of systemic inflammation.
It is noted that the limitations regarding “wherein the method reduces the patient’s serum CRP levels below pre-treatment levels” and “wherein the method reduces, in the patient, one or more pro-inflammatory cytokine serum levels below pre-treatment levels” and “wherein the method reduces the patient’s serum IL-6 levels below pre-treatment levels” and “wherein the serum IL-6 level is decreased by at least 10% compared to pre-treatment levels” and “wherein the serum TNF-α level is decreased by at least 10% as compared to pre-treatment levels” and “wherein the serum TNF-α level is decreased by at least 20% as compared to pre-treatment levels” and “increases the expression level of PCG-1α in the lungs as compared to pre-treatment levels” are obvious to occur since all the elemental steps of the method have been taught by the cited prior art. Since the same claimed patient population is being administered the same claimed active agent, these limitations drawn to mechanisms of action that will obviously occur in vivo.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam 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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/Yong S. Chong/Primary Examiner, Art Unit 1623