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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/31/2026 has been entered.
Claims 1, 2, 6, 7, 15, 20, 41, 45 and 48 are amended, claims 3, 5, 12, 14, 16-19, 24, 30, 32, 33, 36, 38, 44 and 64 are newly canceled and claims 65-83 are new. Claims 1, 2, 6, 7, 15, 20, 41, 45, 48 and 65-83 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/31/2026 considered by the examiner, except where lined through. Several references were lined through because the IDS did not contain a date for them, and the dates could not be ascertained from the information provided.
Objections/Rejections Withdrawn
Any previous rejections over claims 3, 5, 12, 14, 16-19, 24, 30, 32, 33, 36, 38, 44 and 64 are hereby withdrawn in response to Applicant’s cancelation of those claims.
Claim Rejections - 35 USC § 103
The following rejections under 35 USC 103 are withdrawn upon further consideration. Specifically, Applicant’s argument at p. 11, 1st paragraph of the Remarks filed 08/31/2026 that the secondary reference by Han (WO2016/171948) does not teach the same L79D ActIIB mutant, and therefore, cannot be used to suggest an appropriate dose regimen, is persuasive. In addition, according to instant specification at paragraph [00134], the L79D mutant retains “GDF-11 binding while demonstrating greatly reduced activin binding”, which is not taught or suggested in Han.
The rejection of claims 1, 2, 6, 7, 15, 45 and 48 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).
The rejection of claims 20 and 41 are rejected under 35 U.S.C. 103 as being unpatentable Kumar (WO 2018/022762—on IDS filed 06/07/2023) and Han (WO2016/171948) as applied to claims 1, 2, 6, 7, 15, 45 and 48 above, and further in view of Pardanani et al. (Blood, (21 Oct 2013) Vol. 122, No. 21. Abstract Number: 4047).
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, 2, 6, 7, 15, 45, 48, 65-67 and 69-83 are rejected under 35 U.S.C. 103 as being unpatentable over Kumar (WO 2018/022762—of record) in view of Platzbecker et al. (Lancet Oncol 2017; 18: 1338-47). 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 SEQ ID NO: 9:
ID BFA12468 standard; protein; 360 AA.
AC BFA12468;
DT 22-MAR-2018 (first entry)
DE Human ActRIIB-Fc fusion protein, SEQ 50.
KW ActRIIB protein; Immunoglobulin; Tissue plasminogen activator; anemia;
KW antianemic; enzyme inhibition; fusion proterin; prophylactic to disease;
KW therapeutic.
OS Homo sapiens.
OS Synthetic.
CC PN WO2018022762-A1.
CC PD 01-FEB-2018.
CC PF 26-JUL-2017; 2017WO-US043967.
PR 27-JUL-2016; 2016US-0367289P.
CC PA (ACRO ) ACCELERON PHARMA INC.
CC PI Kumar R, Venkata Sai Rajasekhar Suragan;
DR WPI; 2018-092214/13.
CC PT Treating, preventing, or reducing progression rate and/or severity of
CC PT myelofibrosis or at least one complications of myelofibrosis, comprises
CC PT administering activin receptor type IIB antagonist.
CC PS Claim 78; SEQ ID NO 50; 181pp; English.
CC The present invention relates to a method for treating, preventing, or
CC reducing progression rate and/or severity of myelofibrosis or
CC complications of myelofibrosis. The invention also provides: a method for
CC treating anemia in a patient treated with a Janus kinase inhibitor; and a
CC method for increasing red blood cell levels and/or hemoglobin levels in a
CC patient treated with a Janus kinase inhibitor. The present sequence
CC represents a human ActRIIB mature extracellular domain-Fc fusion protein
CC with a TPA leader peptide, which can be used in the method for treating
CC anemia.
SQ Sequence 360 AA;
ALIGNMENT:
Query Match 100.0%; Score 1868; Length 360;
Best Local Similarity 100.0%;
Matches 335; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWDDDFNC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 26 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWDDDFNC 85
Qy 61 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTGGGTHTCPPCPAP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 86 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTGGGTHTCPPCPAP 145
Qy 121 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 146 ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 205
Qy 181 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 206 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 265
Qy 241 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 266 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 325
Qy 301 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 335
|||||||||||||||||||||||||||||||||||
Db 326 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 360
The ActRIIB ligand trap taught by Kumar has a GGG linker (bolded and underlined above), thereby meeting the limitations of new claims 65, 77 and 83. 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 of Kumar). 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). The contemplated JAK inhibitor is fedratinib (see 43, 66; p. 6, line 18; p. 10, line 31; p. 13, line 2; p. 111, line 7). 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 that baseline(s) “for one or more hematologic parameters may be established…” (see p. 122, 1st paragraph). Kumar discloses that risk is determined according to the dynamic international prognostic scoring system (DIPSS—see claims 26-30). Kumar also teaches 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), thereby suggesting the beneficial effects recited in new claim 67.
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, 1.33 mg/kg or 1.75 mg/kg ActRIIB ligand trap once every 21 days as recited in amended claim 1. Second, Kumar does not expressly teach dosing parameters recited in the claims.
(i) Regarding administering 1 mg/kg, 1.33 mg/kg or 1.75 mg/kg of ActRIIB ligand trap once every 21 days, Platzbecker et al. teach a dose escalation study for luspatercept for treating patients with myelodysplastic syndromes. Using the instant specification as a lexicon, luspatercept is the name of the recited ActRIIB ligand trap consisting of instant SEQ ID NO: 11 (see p. 101, description of SEQ ID NO: 11). Platzbecker et al. teach subcutaneously administering luspatercept every 21 days in doses ranging from 0.125-1.75 mg/kg (see abstract and p. 1340, left column and Figure 1):
In the base study, all patients received up to five doses (over a maximum of 12 weeks) of luspatercept treatment at one of seven prespecified dose concentrations ranging from 0.125 mg/kg to 1.75 mg/kg (0.125, 0.25, 0.50, 0.75, 1.00, 1.33, and 1.75 mg/kg; Figure 1).
Therefore, Platzbecker et al. teach the limitations of amended claim 1.
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 using the dosing regimen taught by Platzbecker and colleagues because they teach that the doses between 0.75-1.75 mg/kg were “deemed therapeutic (see p. 1342, right column, last paragraph). The person of ordinary skill in the art would have been motivated to use the ActRIIB ligand trap treatment regimen taught by Platzbecker et al. because the patients receiving the 0.75-1.75 mg/kg doses, a range that encompasses the claimed dose range “achieved IWG HI-E [International Working Group haematological improvement-erythroid] across both the base and extension studies” (see and p. 1343, paragraph bridging left and right columns). Furthermore, the person of ordinary skill in the art could have reasonably expected success in implementing the dosing regimen taught by Platzbecker et al. because these patients had “substantial decreases in transfusion requirements” (see p. 1346, left column, 2nd paragraph).
(ii) Regarding obtaining a baseline hemoglobin level prior to administration of the first dose of ActRIIB ligand trap in the human subject and measuring hemoglobin levels and assessing the RBC transfusion dependence in the human subject prior to each subsequent dose of the ActRIIB ligand trap, both Kumar and Platzbecker et al. disclose measuring parameters at baseline and monitoring during treatment. Kumar teaches monitoring “hematologic parameters during treatment in order to evaluate whether to adjust the dosage during treatment” as well as effects on red blood cells (see paragraph bridging pages 24-25; p. 112, last paragraph; p. 120, lines 20-29; p. 122, whole page). Further, Kumar teaches that hemoglobin levels can be measured by “art-recognized methods” (see p. 112, lines 27-32; paragraph bridging pages 120-121). 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”. In addition, Platzbecker et al. teach measuring baseline hemoglobin and RBC transfusion burden as well as monitoring during treatment (see abstract; p. 1341, Table 1; p. 1342, Table 2; p. 2, section 1.3 of the Appendix). Platzberger et al. teach that hemoglobin concentrations ranged from 6.4-10.1 g/dL, thereby falling within the concentration levels recited in new claims 66, 75 and 82.
Instant claim 15 is interpreted as a description of anemia severity and monitoring the need for RBC transfusion is used to score disease severity (see p. 109, lines 11-21 of Kumar). The teachings of Kumar and Platzbecker et al. strongly suggest that hemoglobin and RBCs can be measured at baseline and during treatment to measure progress or adjust doses. 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). Platzbecker et al. teach (paragraph bridging pages 2-3 of the Appendix):
Secondary efficacy was evaluated using the intent-to-treat population (defined as all patients who received at least one dose of study drug) and the efficacy-evaluable population. Modified HI-E analysis was performed using the intent-to-treat population. Improvements must have lasted ≥8 weeks and they were defined in LTB patients as a haemoglobin increase of ≥1.5 g/dL from baseline, and in HTB [high transfusion burden] patients (haemoglobin level ≤9.0 g/dL) as a reduction of ≥4 RBC units transfused during any 8-week period on study compared with the 8-week period prior to treatment. Time to and duration of modified HI-E and HI-E response were assessed per International Working Group 2006 criteria.
Therefore, both Kumar and Platzbecker et al. teach assessing patients during treatment.
Regarding new claim 73, while the combined teachings of Kumar and Platzbecker et al. do not explicitly teach increasing the ActRIIB ligand trap dose to 1.75 mg/kg after an assessment at 6 weeks showing the subject has had one or more RBC transfusions or has had a hemoglobin level increase of less than 1 g/dL from baseline and decreasing the ActRIIB ligand trap dose to 1 mg/kg every 21 days after an assessment at 3 weeks showing the subject has had a Hgb level increase of greater than 2 g/dL from baseline and has received no RBC transfusions, they strongly suggest this. Kumar teaches that assessments should be made throughout treatment to evaluate appropriate dosing for a patient (see p. 120, lines 20-29). In addition, Platzbecker et al. teach that patients in their extension study could have their doses titrated up to the 1.75 mg/kg dose (see abstract; p. 1340, right column, 1st paragraph).
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to adjust doses based upon measurement and monitoring of hemoglobin levels and RBC burden because Kumar teaches that if monitoring shows adverse effects on hemoglobin levels or RBCs, the dose could be reduced (see p. 122, 2nd paragraph). Similarly, Platzbecker et al. explicitly teach increasing the doses in patients to a more effective dose. The person of ordinary skill in the art would have been motivated to monitor prognostic endpoints prior to and during treatment so that treatment can be adjusted treatment based on changes in the endpoints. The person of ordinary skill in the art in the field of medicine is generally motivated to provide the best possible care at the optimal dose. Furthermore, the person of ordinary skill in the art could have reasonably expected success because monitoring was routine in the art prior to the time of filing of the invention and because Platzbecker et al. set forth the optimal dose range.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 20, 41 and 68 are rejected under 35 U.S.C. 103 as being unpatentable Kumar in view of Platzbecker et al. as applied to claims 1, 2, 6, 7, 15, 45, 48, 65-67 and 69-83 above, and further in view of Pardanani et al. (Blood, (21 Oct 2013) Vol. 122, No. 21. Abstract Number: 4047—of record. 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 Platzbecker et al. and how they meet the limitations of claims 1, 2, 6, 7, 15, 45, 48, 65-67 and 69-83 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 Platzbecker et al. do not teach the subject has been treated with fedratinib for at least 8, 16, 24, 32 or 40 weeks immediately prior to the administration of the first dose of the ActRIIB ligand trap (instant claim 20), or that the fedratinib is administered at a dosage of 400 mg/day, 300 mg/day, 200 mg/day or 100 mg/day (instant claims 41 and 68).
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 daily 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. 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 arguments at pages 9-13 have been fully considered with respect to the new rejections set forth above but are not found persuasive. The arguments concern the teachings of the reference by Han, which is not part of the currently applied prior art. As noted above, the newly applied secondary reference by Platzbecker et al. teach administering the same ActRIIB agent to the same patient population in the recited dosages.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 6, 7, 15, 20, 41, 45, 48 and 65-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 115-136 of copending Application No. 18/971,571 (the reference application) in view of Platzbecker et al., Kumar, and Pardanani. All references are cited above. The claims of the reference application are drawn to a method for treating myelofibrosis comprising administering to a patient in need thereof an effective amount of fedratinib and an ActRIIB polypeptide comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 53; wherein the polypeptide comprises a D at the position corresponding to position 79 of SEQ ID NO: 1; wherein the patient is administered one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment, wherein the method decreases blood cell transfusions by greater than about 30% for 4 to 8 weeks, increases red blood cell levels and increases hemoglobin levels in the patient, wherein the patient has anemia, wherein the patient is blood cell transfusion-dependent and the method decreases blood cell transfusion burden, wherein the patient has primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis and wherein the ActRIIB polypeptide is administered prior to or after treatment with fedratinib.
The differences between the instant claims and those of the reference application are as follows. First, the claims of the reference application do not teach administering 1 mg/kg, 1.33 mg/kg or 1.75 mg/kg ActRIIB ligand trap once every 21 days as recited in amended claim 1. Second, the claims of the reference application do not teach the assessment and monitoring steps recited in the claims. Third, the claims of the reference application do not teach the subject has been treated with fedratinib for at least 8, 16, 24, 32 or 40 weeks immediately prior to the administration of the first dose of the ActRIIB ligand trap (instant claim 20), or that the fedratinib is administered at a dosage of 400 mg/day, 300 mg/day, 200 mg/day or 100 mg/day (instant claims 41 and 68). These issues are considered in turn.
(i) Regarding administering 1 mg/kg, 1.33 mg/kg or 1.75 mg/kg of ActRIIB ligand trap once every 21 days, Platzbecker et al. teach a dose escalation study for luspatercept for treating patients with myelodysplastic syndromes. Using the instant specification as a lexicon, luspatercept is the name of the recited ActRIIB ligand trap consisting of instant SEQ ID NO: 11 (see p. 101, description of SEQ ID NO: 11). Platzbecker et al. teach subcutaneously administering luspatercept every 21 days in doses ranging from 0.125-1.75 mg/kg (see abstract and p. 1340, left column and Figure 1):
In the base study, all patients received up to five doses (over a maximum of 12 weeks) of luspatercept treatment at one of seven prespecified dose concentrations ranging from 0.125 mg/kg to 1.75 mg/kg (0.125, 0.25, 0.50, 0.75, 1.00, 1.33, and 1.75 mg/kg; Figure 1).
Therefore, Platzbecker et al. teach the limitations of amended claim 1.
It would have been obvious to the person of ordinary skill in the art at the time the invention to use the dosing regimen taught by Platzbecker and colleagues because they teach that the doses between 0.75-1.75 mg/kg were “deemed therapeutic (see p. 1342, right column, last paragraph). The person of ordinary skill in the art would have been motivated to use the ActRIIB ligand trap treatment regimen taught by Platzbecker et al. because the patients receiving the 0.75-1.75 mg/kg doses, a range that encompasses the claimed dose range “achieved IWG HI-E [International Working Group haematological improvement-erythroid] across both the base and extension studies” (see and p. 1343, paragraph bridging left and right columns). Furthermore, the person of ordinary skill in the art could have reasonably expected success in implementing the dosing regimen taught by Platzbecker et al. because these patients had “substantial decreases in transfusion requirements” (see p. 1346, left column, 2nd paragraph).
(ii) 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). The contemplated JAK inhibitor is fedratinib (see 43, 66; p. 6, line 18; p. 10, line 31; p. 13, line 2; p. 111, line 7). 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 that baseline(s) “for one or more hematologic parameters may be established…” (see p. 122, 1st paragraph). Kumar discloses that risk is determined according to the dynamic international prognostic scoring system (DIPSS—see claims 26-30).
Regarding obtaining a baseline hemoglobin level prior to administration of the first dose of ActRIIB ligand trap in the human subject and measuring hemoglobin levels and assessing the RBC transfusion dependence in the human subject prior to each subsequent dose of the ActRIIB ligand trap, both Kumar and Platzbecker et al. disclose measuring parameters at baseline and monitoring during treatment. Kumar teaches monitoring “hematologic parameters during treatment in order to evaluate whether to adjust the dosage during treatment” as well as effects on red blood cells (see paragraph bridging pages 24-25; p. 112, last paragraph; p. 120, lines 20-29; p. 122, whole page). Further, Kumar teaches that hemoglobin levels can be measured by “art-recognized methods” (see p. 112, lines 27-32; paragraph bridging pages 120-121). 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”. In addition, Platzbecker et al. teach measuring baseline hemoglobin and RBC transfusion burden as well as monitoring during treatment (see abstract; p. 1341, Table 1; p. 1342, Table 2; p. 2, section 1.3 of the Appendix). Platzberger et al. teach that hemoglobin concentrations ranged from 6.4-10.1 g/dL, thereby falling within the concentration levels recited in new claims 66, 75 and 82.
Instant claim 15 is interpreted as a description of anemia severity and monitoring the need for RBC transfusion is used to score disease severity (see p. 109, lines 11-21 of Kumar). The teachings of Kumar and Platzbecker et al. strongly suggest that hemoglobin and RBCs can be measured at baseline and during treatment to measure progress or adjust doses. 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). Platzbecker et al. teach (paragraph bridging pages 2-3 of the Appendix):
Secondary efficacy was evaluated using the intent-to-treat population (defined as all patients who received at least one dose of study drug) and the efficacy-evaluable population. Modified HI-E analysis was performed using the intent-to-treat population. Improvements must have lasted ≥8 weeks and they were defined in LTB patients as a haemoglobin increase of ≥1.5 g/dL from baseline, and in HTB [high transfusion burden] patients (haemoglobin level ≤9.0 g/dL) as a reduction of ≥4 RBC units transfused during any 8-week period on study compared with the 8-week period prior to treatment. Time to and duration of modified HI-E and HI-E response were assessed per International Working Group 2006 criteria.
Therefore, both Kumar and Platzbecker et al. teach assessing patients during treatment. Regarding new claim 73, the combined teachings of Kumar and Platzbecker et al. teach that assessments should be made throughout treatment to evaluate appropriate dosing for a patient (see p. 120, lines 20-29). In addition, Platzbecker et al. teach that patients in their extension study could have their doses titrated up to the 1.75 mg/kg dose (see abstract; p. 1340, right column, 1st paragraph).
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to adjust doses based upon measurement and monitoring of hemoglobin levels and RBC burden because Kumar teaches that if monitoring shows adverse effects on hemoglobin levels or RBCs, the dose could be reduced (see p. 122, 2nd paragraph). Similarly, Platzbecker et al. explicitly teach increasing the doses in patients to a more effective dose. The person of ordinary skill in the art would have been motivated to monitor prognostic endpoints prior to and during treatment so that treatment can be adjusted treatment based on changes in the endpoints. The person of ordinary skill in the art in the field of medicine is generally motivated to provide the best possible care at the optimal dose. Furthermore, the person of ordinary skill in the art could have reasonably expected success because monitoring was routine in the art prior to the time of filing of the invention and because Platzbecker et al. set forth the optimal dose range.
(iii) Regarding claims 20, 41 and 68 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 daily 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. 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, when considered in light of the teachings of Kumar, Platzbecker et al. and Pardanani, the claims are not patentably distinct from those of the reference application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
