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 .
Response to Amendment
Applicant’s amendment filed 09/15/2025 is acknowledged. Claims 1, 2, 16, 18-20, 24, 30, 32, 33, 41, 44, 45 and 48 are amended; claims 25 and 28 are newly canceled and claim 64 is new.
Claims 1-3, 5-7, 12, 14-21, 24, 30, 32, 33, 36, 38, 41, 44, 45, 48 and 64 are under examination.
Objections/Rejections Withdrawn
Any previous rejections over claims 25 and 28 are hereby withdrawn in response to Applicant’s cancelation of those claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Drawings
The correction to Figure 1 the drawings was received on 09/15/2025. This drawing is accepted.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 3, 5, 6, 7, 12, 14, 17, 44, 45 and 48 under 35 U.S.C. 102(a)(1) as being anticipated by Kumar (WO 2018/022762—on IDS filed 06/07/2023) is withdrawn in response to Applicant’s amendment of claim 1 incorporating the limitations of now canceled claims 25 and 28, which were not included in this rejection.
Claim Rejections - 35 USC § 103
The rejection of claims 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 38, 44, 45 and 48 under 35 U.S.C. 103 as being unpatentable over Kumar (WO 2018/022762—on IDS filed 06/07/2023) is withdrawn in response to Applicant’s amendment of claims 1 and 2, incorporating the limitations of now canceled claims 25 and 28, which were not included in this rejection.
The following rejections under 35 U.S.C. 103 are withdrawn because the aforementioned rejection upon which they are based is withdrawn. Note, however, that new rejections combining the elements of the previous rejections are made below.
The rejection of claims 20, 24 and 41 as being unpatentable over Kumar (WO 2018/022762—on IDS filed 06/07/2023) as applied to claims 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 38, 44, 45 and 48 above, and further in view of Pardanani et al. (Blood, (21 Oct 2013) Vol. 122, No. 21. Abstract Number: 4047).
The rejection of claims 25, 28 and 36 as being unpatentable over Kumar (WO 2018/022762—on IDS filed 06/07/2023) as applied to claims 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 38, 44, 45 and 48 above, and further in view of Han (WO2016/171948).
New Rejections
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
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.
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 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 36, 38, 44, 45, 48 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Kumar (WO 2018/022762—on IDS filed 06/07/2023) in view of Han (WO2016/171948). This rejection is a reworking of previous rejections made in the Office action mailed 06/16/2025 to accommodate the new limitations in claims 1 and 2, and does not raise new issues. The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Kumar teaches treating myelofibrosis, including complications associated therewith such as anemia, comprising administering an ActRIIB antagonist (i.e., ligand trap) in combination with a Janus kinase (JAK) inhibitor, such as fedratinib (see claims 1-4; 38-43). The contemplated ActRIIB ligand trap is an ActRIIB-Fc fusion protein in which the Fc region is a human IgG1 (see p. 55, lines 18-30; p. 85, lines 3-5; p. 128, lines 128-132, Example 1). Kumar expressly discloses that administration of the formulations may be concomitant (see p. 123, lines 12-14). Kumar teach an ActRIIB ligand trap with 100% sequence identity to instant SEQ ID NO: 11, which encompasses instant SEQ ID NO: 9:
Query Match 100.0%; Score 628; DB 1; Length 335;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWDDDFNC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWDDDFNC 60
Qy 61 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPT 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPT 107
Further, the ActRIIB ligand trap disclosed in Kumar is encoded by the nucleotide sequence of instant SEQ ID NO: 34.
The contemplated patient population includes those with primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis, who may be in need of red blood cell (RBC) transfusions and in whom treatment could reduce or eliminate the need for said RBC transfusions (see p. 106, lines 1-6; p. 112, lines 23-26; p. 113, lines 1-7; claims 17, 18, 23-25 and 55). While the WO document by Kumar contemplates patients who are transfusion-dependent, it also teaches that myelofibrosis patients may have non-transfusion dependent anemia, which may be treated with erythropoiesis stimulating agents (see claim 17; p. 111, lines 19-34). In addition, Kumar teaches monitoring hemoglobin to test for anemia and that administering an ActRIIB antagonist results in increased RBC counts and hemoglobin levels in patients treated with a JAK inhibitor (claims 13, 49, 53; p. 112, lines 27-32). Kumar teaches that “hematologic parameters”, including RBCs and hemoglobin levels, can be measured by “art-recognized methods” and that contemplated normal hemoglobin levels are “10-12.5 g/dl, and typically about 11.0 g/dl” (see p. 112, lines 29-32; paragraph bridging pages 120-121). Kumar teaches ruxolitinib is used to treat the patient population suffering from myelofibrosis, which suggests that patients treated with ruxolitinib are contemplated, particularly since it can lead to anemia, which would necessitate treatment with an ActRIIB-Fc (see p. 142, lines 20-25). Kumar teach a study in a mouse model demonstrating that co-administration with an ActRIIB ligand trap improved RBC counts and hemoglobin levels within four weeks (see paragraph bridging pages 142-143).
The second factor to consider is to ascertain the differences between the prior art and the instant claims. First, the WO document by Kumar does not teach administering 1 mg/kg ActRIIB ligand trap once every 21-day days as recited in amended claim 1 and administering a subsequent ActRIIB ligand trap dose of 0.6, 0.8, 1.0, 1.33 or 1.75 mg/kg (claim 36). Second, Kumar does not expressly teach (a) taking a first measurement of hemoglobin (Hgb) level in a subject; (b) administering to the subject an initial dose of an ActRIIB ligand trap; (c) administering to the subject fedratinib or a pharmaceutically acceptable salt and/or hydrate thereof; (d) taking a second measurement of hemoglobin (Hgb) level in the subject at the end of a first period of time after the administration of the initial dose of an ActRIIB ligand trap; and (e) administering to the subject a subsequent dose of the ActRIIB ligand trap based on the second measurement of hemoglobin (Hgb) level as compared to the first measurement of hemoglobin (Hgb) level, or based on a number of red blood cell transfusion that the subject received during the first period of time as recited in claim 2, timing of measurement as in recited in claim 30 and optimizing dosage as recited in claim 38. Further, Kumar does not expressly teach the number of RBC units received in RBC transfusion as recited in claims 15 and 18, or the outcome of hemoglobin measurements as recited in claims 16 and 19. Finally, Kumar does not teach that the first period of time after which a hemoglobin level is measured (referred to in parts (d) and (e) of claim 2) is 1-6 days or 1-8 weeks as recited in claim 33. These issues will be considered in turn.
(i) Regarding administering 1 mg/kg ActRIIB ligand trap once every 21-day days as recited in amended claims 1 and 2 and administering a subsequent ActRIIB ligand trap dose of 0.6, 0.8, 1.0, 1.33 or 1.75 mg/kg (claim 36), Han teaches treating anemia with ActRIIB ligand trap proteins to treat anemia and myelofibrosis, among other wasting conditions, at a dosing frequency of once every 3 weeks (i.e., 21 days; see abstract; [026]-[027], [0233]; [0245]; claims 31-33). Further, Han teaches doses ranging from 1-2 mg/kg of body weight. It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Kumar by administering the doses according to the dose schedule taught by Han because Han teaches administration of the same agent to the same patient population, therefore, one having ordinary skill in the art would deduce the same treatment regimens could be applied. The person of ordinary skill in the art would have been motivated to use known ActRIIB ligand trap treatment regimens and Han teaches that ActRIIB ligand treatment can be routinely adjusted (see paragraph [0240]-[0241]). For this reason, as well, the person of ordinary skill in the art could have reasonably expected success.
(ii) Regarding the measurement steps recited in claim 2, Kumar strongly suggests these methods. As noted above, Kumar teaches monitoring hemoglobin to test for anemia and that administering an ActRIIB antagonist results in increased RBC counts and hemoglobin levels in patients treated with a JAK inhibitor. Further, Kumar teaches that hemoglobin levels can be measured by “art-recognized methods”. See p. 112, lines 27-32; paragraph bridging pages 120-121; claims 13, 49, 53; p. 112, lines 27-32. Kumar reports that normal hemoglobin levels are “10-12.5 g/dl, and typically about 11.0 g/dl” (p. 112, lines 29-30). Kumar also discloses that it is routine in the art to measure hemoglobin for “prognostic modeling in myelofibrosis”, noting that hemoglobin levels < 10 g/dl is the cutoff for one of the negative end-points when determining low to intermediate risk levels according to two routine scoring systems (see p. 108, lines 8-34), which meets the limitations set forth in claims 16 and 19.
Another endpoint in monitoring is the need for RBC transfusion, which scores severity (see p. 109, lines 11-21). Instant claims 15 and 18, which characterize patients as either having received, prior to ActRIIB-Fc treatment, more (4-12) or fewer transfusions (<4), respectively, is interpreted as a description of anemia severity. It would be obvious to treat patients across the spectrum of anemia with the recited methods, which are designed to treat this condition. In addition, Kumar teaches determining the patient’s risk level at a baseline and that the method disclosed therein can improve myelofibrosis risk progression (see claims 26-30). The teachings of Kumar strongly suggest that when treating the patient, hemoglobin can be measured at baseline, followed by treating the patient with ActRIIB-Fc and fedratinib “either concomitantly or sequentially” (see p. 123, lines 12-14), taking a subsequent hemoglobin measurement and adjusting the dosages as recited in instant claims 2, 30 and 38. Further, regarding claims 32 and 33, Kumar strongly suggests measuring hemoglobin again 4-8 weeks after ActRIIB ligand trap initiation (i.e., at the end of “a first period of time”) because they disclose ActRIIB ligand trap administration reduces the need for blood cell transfusions within 4-8 weeks of treatment start (see p. 9, lines 23-29 of Kumar). The person having ordinary skill in the art would be motivated to check hemoglobin levels within this time period to determine whether transfusion is necessary.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to monitor hemoglobin levels and adjust dosages based upon hemoglobin measurements because Kumar sets forth the criteria for doing so. Although Kumar does not annotate the steps as in claims 2, 30, 33 and 38, the disclosure suggests baseline hemoglobin screening, treating with ActRIIB-Fc and fedratinib, monitoring the effects of treatment by taking subsequent hemoglobin levels, and increasing the doses if hemoglobin levels remain low. The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983) and MPEP 2112.
Further, as noted by the United States Supreme Court, if a person of ordinary skill can implement a predictable variation, §103 likely bars its patentability. “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U.S.C. 103.” KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007). The person of ordinary skill in the art would have been motivated to monitor prognostic endpoints prior to treatment and adjust treatment based on changes in the endpoints because the person of ordinary skill in the art in the field of medicine would want to provide the best possible care at the lowest possible dose. Furthermore, the person of ordinary skill in the art could have reasonably expected success because monitoring anemia in myelofibrosis was routine in the art prior to the time of filing of the invention.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 20, 24 and 41 are rejected under 35 U.S.C. 103 as being unpatentable Kumar (WO 2018/022762—on IDS filed 06/07/2023) in view of Han (WO2016/171948) as applied to claims 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 36, 38, 44, 45, 48 and 64 above, and further in view of Pardanani et al. (Blood, (21 Oct 2013) Vol. 122, No. 21. Abstract Number: 4047). This rejection is a reworking of previous rejections made in the Office action mailed 06/16/2025 to accommodate the new limitations in claims 1 and 2, and does not raise new issues. The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Kumar and Han and how they meet the limitations of claims 1-3, 5-7, 12, 14-19, 21, 30, 32, 33, 36, 38, 44, 45, 48 and 64 are outlined above in the preceding rejection and are hereby incorporated.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Kumar and Han do not teach the subject has been treated with fedratinib for at least 8, 16, 24, 32 or 40 weeks prior to the administration of the initial dose of the ActRIIB ligand trap (instant claim 20), the fedratinib is administered at a dosage of 400 mg/day (instant claim 24), or administering a subsequent dose of fedratinib of 100-300 mg/day (instant claim 41). Pardanani et al. teach a treatment study in which patients with myelofibrosis are treated 48 weeks with fedratinib at a dose of 400 mg/day (see the Background section of the abstract). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Kumar by treating patients having myelofibrosis for 48 weeks (i.e., at least 40 weeks) with fedratinib at a dose of 400 mg because Pardanani et al. teach that 80% of patients achieved a spleen response at the 400 mg dose (see the Results section of the abstract).
The person of ordinary skill in the art would have been motivated to follow the dosage prescriptions set forth in the prior art because 80% of patients achieved a reduction in spleen volume at the 400 mg fedratinib dose. Nevertheless, it would have also been obvious to administer a subsequent dose of fedratinib at a dose of 100-300 mg/day because Pardanani et al. report that there were some side effects, and it is obvious to lower the dosage in those cases. Moreover, Pardanani et al. also administered a 300 mg/day fedratinib dose (see Results section of the abstract). See also MPEP §2144.05(I), which cites In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP §2144.05(II), which cites In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, the person of ordinary skill in the art could have reasonably expected success because the study by Pardanani concludes “treatment with fedratinib results in durable reductions in splenomegaly in patients with MF [myelofibrosis]”.
Thus, the claims do not contribute anything non-obvious over the prior art.
Response to Arguments
Applicant argues at p. 13 that Han does not teach or suggest the methods of amended claims 1 and 2 as a whole because Han lists the doses and dosing frequency as laundry lists. Further, Han discloses that the dosage values and frequency vary with type and severity of condition. Given the broad ranges disclosed in Han, Applicant concludes at p. 14 that the person having ordinary skill in the art would not be motivated to administer 1 mg/kg of ActRIIB once every 21 days together with fedratinib.
This argument has been fully considered, but is not found persuasive. Although Han lists a number of possible ranges of dosages and dosage frequencies, the ranges of 1-2 mg/kg and every three weeks (i.e., 21 days) are clearly and explicitly named. Furthermore, all the dosage ranges cited by Applicant in paragraphs [0241]-[0242] of Han encompass the dosages recited in the instant claims. In addition, one having ordinary skill in the art is motivated to optimize within prior art conditions or through routine experimentation (see MPEP 2144.05(II)(A)). The person of ordinary skill in the art is also motivated to monitor prognostic endpoints prior to treatment and adjust treatment based on changes in the endpoints because the person of ordinary skill in the art in the field of medicine would want to provide the best possible care at the lowest possible dose.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955);…see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”);
Further, Applicant’s arguments do not provide evidence of the criticality of the dose regimen recited in amended claims 1 and 2. For instance, the instant specification discloses administering the ActRIIB ligand trap at a dose ranging from 0.3 mg/kg to 2.0 mg/kg once every 14 to 42 days (see paragraph [00184]). See also:
In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”). (MPEP 2144.05(II)(A).
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Applicant listed WO2018/075747 by Han on the IDS filed 09/15/2025. The ‘747 document by Han discloses administering ActRIIB ligand trap at a dose of 1 mg/kg (paragraph [052]).
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 CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675