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 .
Priority
This application is a U.S. national stage patent application under 35 U.S.C. § 371 of
International Application No. PCT/IN2021/050604, filed on June, 22 2021, which claims the benefit of, and priority to, Foreign Application No. IN202011026726, filed on June 24, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 01, 2025. Claims 2 and 7 are canceled. Claims 1, 3-6, and 8-16 are pending and under examination.
Action Summary
Claims 1, 4-6, 8, 11-12, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (WO2015/184087 A1) in view of Khandelwal et al (Biol Blood Marrow Transplant 23 (2017) 1122–1127), are withdrawn in light of the claim amendment.
Claims 3, 9, 10, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (WO2015/184087 A1) in view of Khandelwal et al (Biol Blood Marrow Transplant 23 (2017) 1122–1127), as applied to claims 1, 4-8, 11-12, and 15-16, in further view of Ali et al (EP 2 926 810 A1) and Bernal-Vazquez et al (CA 2 928 286 A1), are withdrawn in light of the claim amendment.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 nonobviousness.
Claims 1, 4-6, 8, 11-12, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (WO2015/184087 A1) in view of Khandelwal et al (Biol Blood Marrow Transplant 23 (2017) 1122–1127), Jakavi (May 2003, pages 1-22), and Wolfgang et al (WO2016/026974).
Berenson teaches a method of treating or preventing a hematological malignancy in a subject comprising administering to the subject a JAK2 inhibitor, and a glucocorticoid, wherein the JAK2 inhibitor is ruxolitinib. (See claims 1 and 5.) The salt of the compound can phosphoric acid. (See lines 20-24 of page 27.) The hematological malignancy includes multiple myeloma and bone pain as its associated symptom. (See claim 3 and lines 15-16 of page 14.) Moreover, Berenson teaches the patient is a human patient that is diagnosed with JAK2 positive polycythemia rubra vera (PRV). (See Example 6.) The JAK2 inhibitor, thalidomide or a derivative thereof, or glucocorticoid is administered orally to a subject. (See lines 19-20 of page 41.) Furthermore, Berenson teaches the JAK2 inhibitor can be formulated into a liquid dosage form the can include water as a solvent, polyethylene glycol as a solubilizer, and paraben as preservative. (See lines 1-6 and lines 24-26 of page 30.) Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, antioxidants, and citric acid can also be present in the compositions. (See lines 28-31 of page 28 bridging line 6 of page 29.) While Berenson does not specifically teach citric acid as a pH adjusting agent and propylene glycol as a co-solvent, the instant specification defines propylene glycol as a co-solvent and citric acid as a pH adjusting agent. A chemical composition/compound and its properties are inseparable. See in re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Lastly, Berenson teaches the JAK2 inhibitor as the active is between about 1 mg/ml and about 5 mg/ml. (See lines 24-29 of page 38.)
Berenson does not specifically teach ruxolitinib, a solvent, and a preservative for treating graft-versus-host disease and multiple myeloma with bone pain as its associated symptom. Moreover, Berenson does not teach pH of 2.2 to 3.2 (2.7 +/- 0.5).
Khandelwal teaches a method of treating steroid-refractory acute GVHD comprising administering to a pediatric patient orally 5 mg twice daily of ruxolitinib. (See Abstract.)
Jakavi teaches Ruxolitinib phosphate is a white to almost white powder. It is highly soluble in water, most soluble at low pH (pH 3.3) at 37oC. (See Description Section of page 1.)
Wolfgang teaches ruxolitinib is used to treat myelofibrosis, polycythemia vera and hematological malignancies. (See paragraph [0003]) Moreover, Wolfgang teaches Ruxolitinib phosphate is the best soluble salt known so far, but solubility decreases with rising pH. The ratio of the solubility at pH 1.2 to pH 4.5 is 7 and the ratio of pH 1.2 to pH 6.8 is 9. A similar tendency can be observed for Ruxolitinib maleate, but solubility is lower at all pH points, measured with respect to Ruxolitinib sulfate and phosphate. The ratio of the solubility at pH 1.2 to pH 4.5 is 4 and the ratio of pH 1.2 to pH 6.8 is 4 as well. (See paragraph [0023].)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine ruxolitinib in the amount of 1-5 mg/ml on a free base basis with propylene glycol, paraben, citric acid, a sweetener, and a flavoring agent in an oral formulation at a pH 2.7 (+/-) for treating hematological malignancy including myeloma and its associated bone pain symptom and 5 mg ruxolitinib for treating acute GVHD. One would have been motivated to combine ruxolitinib in the amount of 1-5 mg/ml on a free base basis with propylene glycol, paraben, citric acid, a sweetener, and a flavoring agent in an oral formulation at a pH 2.7 (+/-) for treating hematological malignancy including myeloma and its associated bone pain symptom because Berenson teaches ruxolitinib as a JAK2 inhibitor can be mixed or combined with propylene glycol, paraben, citric acid, a sweetener, and a flavoring agent in an oral formulation and because Jakavi and Wolfgang teach the motivation to use the claimed pH. One would reasonably expect the oral formulation comprising ruxolitinib with propylene glycol, paraben, citric acid, a sweetener, and a flavoring agent to treat GvHD and multiple myolema in a pediatric patient successfully. Furthermore, one would be motived to use the 5 mg ruxolitinib for treating acute GVHD because Khandelwal teaches a method of treating acute GVHD comprising administering to a pediatric patient orally 5 mg twice daily of ruxolitinib. One would reasonably expect the method taught by Khandelwal to effectively treat acute GVHD successfully.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/response filed on December 01, 2025
Applicant’s argument
Applicant argues that the instant claims are not obvious over the cited references at least because the references chosen by the Office do not contain each and every element of instantly amended claim 1, nor is there a suggestion or motivation to combine those references to arrive at instantly amended claim 1. For example, Berenson does not indicate any target pH of a ruxolitinib formulation, much less a pH of 2.7 ± 0.5. Khandelwal does not cure the deficiencies of Berenson. Khandelwal is directed to the use of ruxolitinib in the treatment of GVHD in pediatric patients. However, while Khandelwal describes the amount of ruxolitinib administered, Khandelwal does not describe any specific ruxolitinib formulation, much less the specific oral formulation set forth in instantly amended claim 1
Examiner’s response
In response, 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, Berenson and Khandelwal may not well teach each and every element of instantly amended claim 1. However, Jakavi and Wolfgang were cited to show that pH of the solution can be obtained.
Claims 3, 9, 10, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (WO2015/184087 A1) in view of Khandelwal et al (Biol Blood Marrow Transplant 23 (2017) 1122–1127) Jakavi (May 2003, pages 1-22). and Wolfgang et al (WO2016/026974), as applied to claims 1, 4-6, 8, 11-12, and 15-16, in further view of Ali et al (EP 2 926 810 A1) and Shimada et al (BMC Musculoskelet Disord. 2020 Jan 20; 21:44).
The teachings of Berenson, Khandelwal, Jakavi, and Wolfgang have been highlighted in the above rejection.
Berenson, Khandelwal, Jakavi, and Wolfgang collectively do not teach a mixture of methyl paraben and propyl paraben, sucralose, and a strawberry flavor. In addition, Berenson, Khandelwal, Jakavi, and Wolfgang collectively do not teach the specific compositions recited in claims 13 and 14. However, Berenson teaches the JAK2 inhibitor and thalidomide or derivatives thereof, and/or glucocorticoids can be administered separately. (See lines 24-27 of page 19.)
Ali teaches oral liquid formulations are becoming an increasingly important issue in the area of better patient compliance comparative to the conventional solid dosage forms for oral administration such as capsules and tablets, which are the most commonly used. In particular pediatric and geriatric patients and patients who are mentally retarded or nauseated often experience difficulties in swallowing solid dosage forms. Besides, conventional solid dosage forms are not suitable for bedridden or busy and travelling patients, in case the patient may not have easy access to water. Thus, oral liquid pharmaceutical formulations represent an alternative for such patients and provide for a better patient compliance with recommended pharmaceutical therapies. Unlike the solid dosage forms, oral liquid pharmaceutical forms require no dissolution so its absorption is rapid and unaffected by alterations in gastric pH. Therefore, they deliver high concentration of active pharmaceutical agent to the intestinal epithelium and minimize first-pass metabolism. (See paragraph [0009]. Ali also teaches on the other-side, oral liquid pharmaceutical formulations are not easy to process. A satisfied oral liquid dosage form needs to meet number of requirements such as stability, taste and solubility. Active pharmaceutical agents in liquid forms are more susceptible to chemical and physical instability than the solid state. Also trace amounts of impurities coming from active pharmaceutical agents or excipients and the pH of the solution may cause the degradation of active pharmaceutical agent and this may cause stability problems when the solution is consistently introduced into atmosphere. Moreover, oral liquid pharmaceutical formulations should have pleasant taste for the better patient compliance. (See paragraph [0010].) Moreover, Ali teaches an oral liquid pharmaceutical formulation of loxoprofen
PNG
media_image1.png
340
614
media_image1.png
Greyscale
. (See paragraph [0031].) The amount of methyl paraben is 0.1-50 mg/ml, the amount of propyl paraben is 0.1-50 mg/ml, the amount of propylene glycol is 20-150 mg/ml, the amount of citric acid is 0.1-10 mg/ml, the amount of sucralose is 0.1-20 mg/ml, and the amount of aroma is 1-50 mg/ml and q.s. to 1 ml of purified water. Ali teaches the aroma agent is strawberry. (See paragraph [0028].) The amount of each of the inactive ingredients taught by Ali touches the amounts claimed.
Shimada teaches in the macrophage depletion group, dexamethasone, pregabalin, and loxoprofen groups, M1 macrophage infiltration into muscles/bones was significantly lower and muscle weight and total bone density were significantly higher than in the untreated group. M1 macrophage infiltration exacerbates muscle/bone atrophy after peripheral nerve injury. By suppressing M1 macrophages at the neural injury local site, muscle/bone atrophy could be avoided. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the obvious oral formulation taught by Berenson and Khandelwal by selecting a formulation comprising ruxolitinib with the inactive ingredients taught by Ali and further formulating the ruxolitinib taught by Berenson into a phosphate salt crystalline form in the amount taught Berenson to give Applicant’s claimed invention. One would have been motivated to do so, not only because Berenson teaches solvent, preservatives, sweetener, flavoring agent, citric acid, and propylene glycol can be used formulate Ruxolitinib, but also because Ali teaches the inactive ingredients in the amount that encompass the claimed amount wit loxoprofen as the active agent can be used for an oral liquid pharmaceutical formulations should have pleasant taste for the better patient compliance for pediatric patient, and also because Shimada teaches loxoprofen can be used to treat bone pain. One would reasonably expect the oral formulation comprising ruxolitinib phosphate and in amount claimed to be effective for treating polycythemia vera and GvHD with success because both loxoprofen and ruxolitinib are effective to treat bone pain.
With respect to the salt factor of 1.320 claimed. The fact that the Berenson teaches the free base of ruxolitinib and the fact that Bernal-Vasquez teaches the phosphate salt of ruxolitinib, the salt factor of 1.320 is necessarily present because the salt factor is the molecular weight of ruxolitinib phosphate to that of free base ruxolitinib. MW of the free base is 303.37. The molecular weight of the phosphate salt of ruxolitnib is 404.36. Then 404.36 / 306.36 is 1.320.
Applicant’s argument
Applicant argues that even if the cited references disclosed each and every claimed element and included motivation to combine them in a way to arrive at the claimed oral formulation, there is no reasonable expectation that such combination would successfully result in the claimed oral formulation. As noted in the specification, ruxolitinib poses numerous formulation challenges, including a pH dependent solubility (see page 3, lines 6- 12 of the specification as filed). This challenge, in particular, was overcome by inclusion of a pH adjusting agent in an amount to arrive at an overall pH of 2.7 ± 0.5, a limitation now incorporated into amended claim 1. Further, the amount of citric acid in independent claims 13 and 14 result in an oral formulation at pH 2.7 ± 0.3 (see at least, for example, page 9 lines 1-3 of the specification as filed).
Examiner’s response
In response, Applicant’s argument is not persuasive. Specifically, The cited references do not recognize that ruxolitinib poses numerous formulation challenges, including a pH dependent solubility. However, Jakavi and Wolfgang provide a solution to solubilize ruxolitinib by using a low pH. A person of ordinary skill in the art would look into the art (wolfgang, Jakavi, and Ali) for compounds that have solubility problems where the art provide a solution to formulate said compound into a stable oral liquid formulation and for compounds that have similar use such as bone pain treatment.
Conclusion
Claims 1, 3-6, and 8-16 are not allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEAN P CORNET/Primary Examiner, Art Unit 1628