Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/19/2026 has been entered.
Status of Claims
Claims 1 and 7-8 are pending.
Priority
Applicant’s claim for benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. This application is a national stage entry of and claims priority to Application Serial No. PCT/CN2021/102607, filed 6/28/2021. Acknowledgment is made of applicant's claim for foreign priority based on an application CN202010668274.3 filed on 7/13/2020.
Information Disclosure Statement
All references from IDS(s) received 01/13/2023 have been considered unless marked with a strikethrough.
Response to Arguments
Applicant's arguments (labels as doc code ASMB, 12 pages) filed 7/19/2026 have been fully considered and have been found not persuasive.
In a final dated 4/20/2025, Claims 1, 7, and 8 were examined upon their merits.
In a final dated 4/20/2025, Claims 1, 7, and 8 were rejected 35 U.S.C. 103. The Applicant did not amend or cancel any claims.
With respect to the 103 rejection, the Applicant argues the following points:
It is common knowledge to those skilled in the art that JAK2 inhibitors cannot treat ruxolitinib resistance.
The Applicant argues that it is known in the art that the mechanism of ruxolitinib resistance involves JAK1 and TYK2 binding to JAK2 and translocating to activate JAK2 to achieve signal transduction when JAK2 phosphorylation sites are occupied and signal transduction is inhibited. Applicant cites multiple literature sources to back up this argument. Further, the Applicant addresses the prior art provided by the Examiner (“Harrison”) and argues that Harrison teaches fedratinib was used for treating patients who have failed ruxolitinib treatment and that examiner misunderstand and equates “treatment failure” with “drug resistance.” The Examiner agrees that treatment failure and drug resistance have different underlying mechanisms. However, the Examiner argues that Harrison explicitly teaches the use of a JAK2 inhibitor in patients with ruxolitinib resistance. Harrison clarifies the difference between ruxolitinib failure and resistance. Harrison teaches (as pointed out by the Applicant) “There is currently no consensus definition of ruxolitinib failure. What has been described as the “heterogeneity of treatment failure” can include primary resistance (which fortunately seems to be rare), loss of an initial response, intolerance to the drug, or progressive disease during treatment, all of which may be linked to the ruxolitinib dose.” Harrison later teaches that primary resistant to ruxolitnib is uncommon. It is secondary resistance to ruxolitnib that is more common and this secondary resistance is what is considered the definition to ruxolitnib resistance (vs failure which is primary). Later, Harrison teaches an overview of the JAKARTA2 study where 66% of patients were considered by investigators as resistant to ruxolitinib and 33% were deemed ruxolitinib intolerant. Harrison does teach that fedratinib was more effective in intolerant patients over resistant patients however, improvement was still seen in resistant patients with treatment of fedratinib. Although it cannot be used as prior art, for ease of communication of the general findings of Harrison, the Examiners points to Jeyaraju, D. et al. (Blood (2023) 142 (Supplement 1): 1434. https://doi.org/10.1182/blood-2023-181898) as an evidentiary reference where it summarizes Harrisons work to include that fedratinib overcomes ruxolitinib resistance is used as a second line therapy in MF based on efficacy from the JAKARTA2 study. This is used to concisely communicate the Examiner’s interpretation of Harrison and how it is also interpreted by those skilled in the art. Finally, the Examiner does not doubt that other JAK2 inhibitors have not had the same outcomes as fedratinib, however the literature does suggest other JAK2 inhibitors may be effective, as pointed out by the Applicant. Therefore, a person skilled in the art would be motivated to try other inhibitors of the JAK-STAT pathway (such as sorafenib) based on the outcomes of fedratinib.
No single prior art reference discloses or suggests using sorafenib or regorafenib to treat ruxolitinib-resistant MPN
The Applicant argues that the prior art provided by the Examiner either teaches sorafenib’s synergy with ruxolitnib (Barrio) or JAK2 inhibitors in ruxolitinib-resistance (Harrison) but not sorafenib. The Examiner argues that based on the previous argument that it would be obvious to a person skilled in the art to substitute the JAK2 inhibitors, as taught by Harrison, for compounds that are known to treat MPNs and also are known to interact with the JAK-STAT pathway, as taught by Barrio.
The proposed combination of Barrio, Harrison, and del Campo is improperly constructed with hindsight and 4. Del Campo does not teach that sorafenib is an effective JAK inhibitor for treating MPN cells and 5. The three references serve contradictory objectives and cannot be rationally combined
The Applicant argues a person skilled in the art would not have been motivated to combine a study about drug-sensitive cells (Barrio) with a study about drug-resistant patients (Harrison) to arrive at a method of treating drug-resistant disease. The Examiner argues that Barrios teachings are that sorafenib is known to treat MPNs (limitation 1 of the independent claim), and Harrison teaches that JAK2 inhibitors can overcome ruxolitinib-resistance in MPNS (limitation 2 of the independent claim) and finally, sorafenib can act on the JAK-STAT pathways, as taught by Del Campo, which serves as the motivation to combine the two teachings above of the required limitations of the claim.
6. Secondary considerations
a. The Applicant argues that the instant application shows superior results. The Applicant argues:
“The invention provides the first demonstration that sorafenib and regorafenib effectively inhibit proliferation and promote apoptosis in ruxolitinib-resistant MPN cell models (HELPE and HELRE). The resistance indices were 510 and 498 respectively, demonstrating high-level ruxolitinib resistance. Despite this extraordinary resistance, sorafenib's IC₅₀ values were only 2.80 µM and 3.56 µM in these highly resistant models-demonstrating remarkable potency.”
The Examiner understands the Applicant’s point. The Examiner suggests an affidavit/declaration/etc. comparing the results on the instant application to the prior art on why it would be not obvious to a person skilled in the art. This would strengthen the superior results argument.
Other (A-C).
A-B. Claims 7-8 are not obvious. The Applicant argues that Claims 7-8 depend from claim 1 and add the limitations that it is a medicament with a pharmaceutically acceptable excipient and is an oral/injection preparation. The Applicant argues that this is supported by Harrison and the BMS Package insert cited by the Examiner. The Examiner does not understand the Applicants argument as it seems they are agreeing with the Examiner.
C. Regorafenib is not rendered obvious by Fogelman. The Applicant argues that Fogelman studies ruxolitinib combined with regorafenib for mCRC not MPN. The Applicant argues these are biologically very different. The Examiner agrees that these are fundamentally different. The Examiner recites Fogelman which teaches “regorafenib is an oral multi-targeted kinase inhibitor that targets angiogenic, stromal, and oncogenic receptor tyrosine kinases.” The Examiner originally felt this would fall under the category for substitution with a JAK2 inhibitor but in light of the arguments on sorafenib, the Examiner finds a lack of motivation for a person skilled in the art to use regorafenib. Therefore, this art is withdrawn, however since the claim includes sorafenib or regorafenib, the rejection is maintained.
NEW/MAINTAINED REJECTIONS
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 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 1 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Barrio, S. et al. (British Journal of Haematology, 2013, 161, 667–676; “Barrio”) in further view of Harrison, C. et al. (Ann Hematol. 2020 Mar 20;99(6):1177–1191.; “Harrison”) and del Campo, S. et al. (J Immunol. 2015 Aug 3;195(5):1995–2005; “del Campo”) as evidenced by the Bristol-Myers Squibb Package Insert (https://packageinserts.bms.com/pi/pi_inrebic.pdf).
Barrio teaches sorafenib as a potential treatment for myeloproliferative neoplasms (MPNs) (Abstract) including assessment of patients with polycythemia vera (Introduction, first para.), as required by instant claims 1. Barrio also teaches the ability of sorafenib to inhibit the proliferation of (Abstract and Fig 2), as well as promote the apoptosis of HEL cells (Suppl. Fig 2C).
Barrio also teaches a synergistic effect between sorafenib and ruxolitinib, but fails to teach treating ruxolitinib-resistant MPNs with sorafenib.
Harrison teaches that JAK2 inhibitors, such as fedratinib, pacritinib, and momelotinib, have been shown to induce clinical responses in patients with ruxolitinib resistance. Harrison also teaches the patients with ruxolitinib-resistant MPNs may be secondary to polycythemia vera (Introduction, para. 1). Harrison also teaches the oral administration of fedratinib being used as a medicament (Table 2), as required by instant claim 8. Finally, Harrison teaches the FDA approved version of fedratinib is INREBIC ® which includes excipients such as silicified microcrystalline cellulose and sodium stearyl fumarate, as evidenced by the BMS Package insert (Page 5, “Description” section).
Harrison fails to teach sorafenib. However, Barrio teaches sorafenib as a possible JAK2 inhibitor. Along the same line, Del Campo teaches that sorafenib inhibits JAK-STAT signal transduction. Specifically, del Campo proposes that sorafenib inhibits cytokine-induced JAK-STAT activation via inhibition of JAK (Discussion, Para. 3). Therefore, because inhibition of JAK-STAT seemingly improves ruxolitinib resistance, as taught by Harrison, it would be obvious to use sorafenib to treat myeloproliferative neoplasms having ruxolitinib resistance. Therefore, because sorafenib can inhibit the same pathway as fedratinib, as well as due to its synergistic effects with ruxolitinib, a person skilled in the art would be motivated to extract the method of Barrio and apply the teachings of Harrison to arrive at the current invention.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A), it would have been prima facie obvious to extract the method of Barrio and use sorafenib to treat ruxolitinib-resistant MPN, as well as administer sorafenib as a medicament, based on the teachings of Harrison. A person skilled in the art would be motivated to do so because Harrison teaches JAK2 inhibitors as medicaments to treat ruxolitinib-resistant MPN and sorafenib works to inhibit JAK2. Therefore, claims 1 and 7-8 would be obvious to a person skilled in the art at the time.
Applying KSR example rationale (B), it would have been prima facie obvious to extract the method of Barrio and substitute sorafenib for different JAK inhibitors, as taught by Harrison. A person skilled in the art would be motivated to do so because Harrison teaches JAK2 inhibitors as medicaments to treat ruxolitinib-resistant MPN and sorafenib works to inhibit JAK, as taught by del Campo. Therefore, claims 1 and 7-8 would be obvious to a person skilled in the art at the time.
Conclusion
Claims 1 and 7-8 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICOLA MARIA BAUER whose telephone number is (703)756-1269. The examiner can normally be reached Monday-Friday 7:30-5 EST.
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/N.M.B./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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