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 .
This is a Non-Final Office Action.
Election/Restrictions
Applicant's election without traverse of Group I in the reply filed on October 25, 2024 is acknowledged. Group I, drawn to a deuterated pyrrolo[2,3-d]pyrimidine, and compositions thereof, embraced by claims 10-21 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the classification of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant elects the following species:
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as the phosphate salt.
Claims 10-21 are pending and under consideration.
Claim Rejections - 35 USC § 112
The rejection of claim 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the preamble stating “The method of claim 18” but claim 18 being drawn to a pharmaceutical composition, is withdrawn based on the amendments.
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 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.
Claim Rejections - 35 USC § 103
The rejection of claims 10-21 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rodgers et al. (US 7598257) in view of Dyck et al. (Journal of Neurochemistry, 1986, Volume 46 Issue 2, pp. 399-404), US 6,603,008, US 6221335, US 20070082929, US 20070197695, US 7517990, 20050107420, Tonn et al. (Biological Mass Spectrometry, 1993, Volume 22 Issue 11, pp. 633-642), Haskins et al. (Biomedical Spectrometry, 1982, Volume 9 Issue 7, pp. 269-277), Wolen et al. (Journal of Clinical Pharmacology, 1986; 26, pp. 419-424), Browne et al. (Journal of Clinical Pharmacology, 1998, 38, pp. 213-220), Baillie (Pharmacology Rev., 1981, 33, pp. 81-132), USP 6440710, Gouyette et al. (Biomedical And Environmental Mass Spectrometry, 1988, Vol. 15, pp. 243-247), Cherrah et al. (Biomedical and Environmental Mass Spectrometry, 1987, Volume 14 Issue 11, pp. 653 – 657), Pieniaszek et al. (J. Clin. Pharmacol, 1999, 39, pp. 817-825), Honma et al. (Drug Metab. Dispos, 1987, 15 (4), pp. 551) and Berge et al. (Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19), is withdrawn.
The rejection of claims 10-21 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rodgers et al. (US 7598257) in view of Schilling et al. (Drug Metabolism and Disposition, 2010, 38(11), pp. 2023-2031) and Berge (Journal of Pharmaceutical Sciences, 1977, vol. 66, no. 1, pp, 1-19), is withdrawn.
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 v. 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 10-21 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rodgers et al. (US 7598257) in view of Rodgers’ et al. (US 20080312259), Concert Backgrounder (2007, provided on the IDS), Schilling et al. (Drug Metabolism and Disposition, 2010, 38(11), pp. 2023-2031), and JAKAFI® label (2011, provided on the IDS).
The instant application claims compound 111 or a pharmaceutically acceptable salt thereof, e.g., a phosphate salt, wherein each position in the compound designated specifically as deuterium has at least 90% incorporation of deuterium.
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.
The ‘257 patent teaches the following compound:
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, see claim 2 of the ‘257 patent. The primary reference teaches the phosphate salt in the Remington’s Pharmaceutical Sciences reference, which is incorporated by reference in its entirety, see column 32, lines 64-67.
The phosphate salt of the compound shown above, (also known as ruxolotinib or Jakafi®), is also taught in the ‘259 application, see page 6, Example 2.
Ruxolinitinb is an FDA approved drug with common adverse reactions associated with the use of it that include thrombocytopenia, anemia, bruising, dizziness and headache, as noted by Jakafi® label (ruxolitnib).
Neither the ‘257 patent or the ‘259 publication teach the claimed compound with a deuterium incorporation of at least 90%, which is more than the natural abundance of deuterium. Thus, the only difference between the claimed and cited compound is H versus Applicant's deuterium of at least 90% on the cyclopentyl ring.
As first branch, one is motivated to prepare deuterated versions of drugs to obtain a version with better pharmaceutical properties. Secondly, and as an alternative branch, one is motivated to prepare deuterated versions of drugs, which can be used to obtain valuable information about how the un-deuterated drug or closely related drugs act in the body.
The Concert Backgrounder is a marketing publication issued by Applicant. It teaches that deuteration of compounds provides the potential for improved safety, better tolerability, and enhanced efficacy. "[S]ince deuterium is heavier than hydrogen, it forms significantly stronger bonds with carbon resulting in differentiated ADME (Adsorption, Distribution, Metabolism, and Excretion)… [Hence,] [d]euterium substitution has the potential to create NCEs [new chemical entities] with improved safety, tolerability and efficacy."). The Concert Backgrounder observes that "the magnitude and nature of the deuterium benefit cannot be predicted a priori," so it is necessary to first "test multiple compounds in a range of assays to identify those that are differentiated." It further emphasizes, however, that "[d]euteration provides novel agents with the potential for ... [i]mproved safety[,] ... [b]etter tolerability[,] .. . [and] [e]nhanced efficacy, " adding that Concert “is deploying its product technology platform to rapidly assemble a pipeline of valuable new deuterated drugs."
Thus, one is motivated to prepare deuterated drugs to gain these explicitly set forth advantages. This provides a strong motivation, to obtain these advantages.
Hence, it is clear that under either of these two branches, “a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and that there would have been a reasonable expectation of success." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641, 1645.
Moreover, given that there is always a need to enhance the pharmacological effects of a compound (e.g. increased in vivo half-life) without significantly altering its basic chemical structure (first branch), or that there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g. measure bioavailability or identify metabolites) (second branch), and that there is only a limited number of ways that this can be done, it would be obvious to pursue a potential solution that has a reasonable expectation of success. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O’Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
In addition, it is clear under both branches that deuteration per se is a known improvement technique for getting a more useful version of the pharmaceutical, and that the improvement is of a predictable nature. Thus, it would have been obvious to one of ordinary skill in the pharmaceutical art to have applied this known improvement technique in the same way to the compound of the primary reference to obtain the results reasonably predictable from the secondary references. See e.g., KSR International Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500.
As for the specific deuterated locations on the molecule, Shilling et al. disclose known in vivo metabolites of ruxolitinib, where 3 out of 5 oxidized metabolites occur on the cyclopentyl ring, Therefore, Shilling teaches a POSA that the oxidative metabolism “hotspot” on ruxolitinib is the cyclopentyl ring, and this is not prone to switching to a different portion of the molecule (metabolic switching).
Furthermore, a POSA would have deuterated at the site corresponding to Y2 and/or Y3 in Formula A or Formula I of the claims of the ’149 patent. In each instance, one would have deuterated at every Y2 and/or every Y3. This is because the number of deuterated compounds that a POSA would prepare to test is not large, especially in light of the information in Shilling describing the known metabolites of ruxolitinib. It would make no scientific sense to deuterate selectively only some or one of the sites of the cyclopentyl ring (i.e., some of Y2 or some of Y3) because Shilling explains that metabolism occurs at each of the four secondary methylenes of the cyclopentyl ring. Furthermore, deuterating at only some of Y2 or Y3 would result in the formation of unwanted diastereomers and would leave C-H bonds at that same position (i.e., Y2 or Y3) that would still be prone to metabolism. Thus, given the known metabolic “hotspots” on the cyclopentyl moiety of ruxolitinib, the most reasonable deuterated analogs would have been the derivatives shown below:
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and specific enantiomers of 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-yl-1-yl]propanenitrile given the known metabolic “hotspots” on the cyclopentyl ring, as described by Shilling.
Schilling also teaches “7HPyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424[, ruxolitinib or Jakafi®]) is an orally active and potent inhibitor of JAKs with greater than 100-fold selectivity against a panel of 26 non-JAK kinases and is in development for the treatment of myeloproliferative neoplasms… INCB018424 has demonstrated efficacy in myelofibrosis, the most serious of the chronic myeloproliferative neoplasms for which there is no approved therapy,” see page 2023, first paragraph.
Therefore, it would be obvious to treat myelofibrosis with a deuterated analog of ruxolitinib because Rodgers teaches the un-deuterated compound and the deuterated compound at the natural abundance level as a treatment for myelofibrosis. Moreover, Concert teaches the motivation to deuterate generally and deuterating on the cyclopentyl ring of ruxolitinib is taught by Shillings as “hot spots” for ruxolitinib.
Thus, said claims are rendered obvious by the above references.
Declarations by Dr. Julian Mackay-Wiggan and Dr. Scott Harbeson were received on October 2, 2025. Since the above rejection is a new rejection, the declaration will be reviewed if Applicant finds the declarations are still required to address the rejection.
Conclusion
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624