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 12/18/2025 is acknowledged. Claims 7 and 27 are amended, claims 11, 28, 51, 55, 73, 98 and 118 are newly canceled and claims 146-163 are new. All non-elected claims have been canceled. Claims 7, 27 and 146-163 are under examination.
Effective Filing Date
Based on an inspection of the prior applications, claims 7, 27, 146-148, 154-157 and 163 are supported by the disclosures of at least provisional application serial no. 62/992,891 as well as PCT/US2021/023335. Claims 151, 152, 161 and 162 are supported by the disclosures of at least provisional application serial no. 63/029,447, claims 149, 150, 158 and 159 are supported by at least provisional application serial no. 63/086,835 and claims 151 and 160 were first disclosed in PCT/US2021/023335.
The effective filing date of claims 7, 27, 146-148, 154-157 and 163 is 03/20/2020.
The effective filing date of claims 151, 152, 161 and 162 is 05/23/2020.
The effective filing date of claims 149, 150, 158 and 159 is 10/02/2020.
The effective filing date of claims 151 and 160 is 03/19/2021.
Rejections Withdrawn
Any previous rejections over claims 11, 28, 51, 55, 73, 98 and 118 are hereby withdrawn in response to Applicant’s cancelation of those claims.
Claim Rejections - 35 USC § 103
The rejection of claims 7 and 27 under 35 U.S.C. 103 as being unpatentable over Sung et al. (WO 2014066487—on IDS filed 09/25/2023) in view of Seehra (WO 2018089715—on IDS filed 09/25/2023) is withdrawn in response to Applicant’s amendment. The claims have been amended to recite treatment of subjects with an ActRIIa variant (SEQ ID NO: 69) who have or at risk of developing thrombocytopenia (claim 7) or neutropenia (claim 27) associated with myelodysplastic syndrome, myelofibrosis or myelofibrosis treatment (claim 7) or associated with a myelodysplastic syndrome or myelofibrosis (claim 27), which the applied prior art does not teach or suggest.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over Seehra (WO 2018089715—on IDS filed 09/25/2023) in view of Liebman (Thrombosis Research 133 S2 (2014) S63–S69) is withdrawn in response to Applicant’s amendment. Claim 7 is amended to recite the thrombocytopenia “is associated with a myelodysplastic syndrome, myelofibrosis or myelofibrosis treatment”, which the applied prior art does not teach or suggest. Rather, the combined teachings of Seehra and Liebman suggest that that the thrombocytopenia is a common consequence of cancer treatment.
The rejection of claim 27 under 35 U.S.C. 103 as being unpatentable over Seehra (WO 2018089715—on IDS filed 09/25/2023) in view of Lustberg, Clin Adv Hematol Oncol. Author manuscript; available in PMC 2014 June 16; 5 pages) is withdrawn in response to Applicant’s amendment. Claim 27 is amended to recite the neutropenia “is associated with a myelodysplastic syndrome or myelofibrosis”, which the applied prior art does not teach or suggest. Rather, the combined teachings of Seehra and Lustberg suggest that the neutropenia arises as a result of cancer treatment.
Double Patenting
The following rejections on the ground of nonstatutory double patenting are withdrawn in response to Applicant’s amendment. New rejections are made below in order to address the amendment and the new claims.
The rejection of claims 7 and 27 as being unpatentable over claims 1-11 of U.S. Patent No. 12,364,737.
The provisional rejection of claims 7 and 27 as being unpatentable over claims 92-99 and 102 of copending Application No. 18/390,085.
The provisional rejection of claims 7 and 27 as being unpatentable over claims 1-5, 18, 23, 24, 27, 32, 35, 41-43, 45 and 48 of copending Application No. 18/443,987.
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 7, 27, 146-149, 152, 153, 155-158, 161 and 162 are rejected under 35 U.S.C. 103 as being unpatentable over Attie et al. (WO 2016/090077) in view of Seehra (WO2018/089715—on IDS filed 09/25/2023). The claims have been amended to recite treatment of subjects with an ActRIIa variant (SEQ ID NO: 69) who have or at risk of developing thrombocytopenia (claim 7) or neutropenia (claim 27) associated with myelodysplastic syndrome, myelofibrosis or myelofibrosis treatment (claim 7) or associated with a myelodysplastic syndrome or myelofibrosis (claim 27). This rejection is necessitated by Applicant’s amendment.
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. Attie et al. teach methods of treating patients with a blood disorder such as anemia, myelodysplastic syndromes, thrombocytopenia or neutropenia with an ActRII inhibitor (see claims 1, 2; paragraphs [00121]; [00123]; [00131]-[00132]), wherein the ActRII inhibitor is an ActRIIa polypeptide, wherein the polypeptide further comprises an Fc domain, such as a humanized fusion-protein consisting of the extracellular domain of ActRIIa and the human IgG1 Fc domain (see paragraphs [0034]; [0037]; [00219]; [00181]-[00220]; claims 109-110 and SEQ ID NO: 12). Attie et al. teach that the contemplated ActRII inhibitors prevent inappropriate activin signaling (see paragraphs [0003]; [0006]; [00177]). The second factor to consider is to ascertain the differences between the prior art and the instant claims. Attie et al. do not teach their ActRIIa polypeptide has the sequence set forth in SEQ ID NO: 69.
Seehra teach treatment of bone loss with an extracellular ActRIIa variant having a sequence with 100% identity to SEQ ID NO: 69:
Query Match 100.0%; Score 625; Length 109;
Best Local Similarity 100.0%;
Matches 109; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYATWRNISGSIEIVKKGC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYATWRNISGSIEIVKKGC 60
Qy 61 WLDDFNCYDRTDCVETEENPQVYFCCCEGNMCNEKFSYFPEMEVTQPTS 109
|||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 WLDDFNCYDRTDCVETEENPQVYFCCCEGNMCNEKFSYFPEMEVTQPTS 109
See claims 109-111 and the Table at p. 27 of Seehra. Seehra et al. also teach that the linker is a flexible linker and may be GGG (see p. 33, lines 27-41 through p. 34, line 1; claim 95). Seehra teaches that the Fc domain may be an IgG1 fused to the C-terminus of the ActRIIa polypeptide (see p. 1, lines 25-27; p. 3, lines 18-19; p. 13, lines 12-14).
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 Attie et al. by using the ActRIIa variant taught by Seehra because Seehra teaches the ActRlla variants disclosed therein have “improved properties” such as a greater half-life and solubility (see p. 39, lines 30-35). The person of ordinary skill in the art would have been motivated to make the substitution because the modified ActRIIa variants can be used to treat many “conditions in which elevated activin signaling has been implicated” (see p. 39, lines 36-41 of Seehra). 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. For the same reason, if a technique has been used to improve one method (i.e., an improved ActRIIa variant for treatment), and a person of ordinary skill would recognize that it would improve similar methods (i.e., treatment of disease related to excessive activin signaling) in the same way, using the technique is obvious unless its actual application is beyond his or her skill (KSR, 127 S. Ct. at 1740). “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). Given the improved half-life and solubility of the modified soluble extracellular ActRIIa variants taught by Seehra, the person of ordinary skill in the art could have reasonably expected success when substituting this soluble extracellular ActRIIa variant for the one taught by Attie and colleagues.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 150, 151, 159 and 160 are rejected under 35 U.S.C. 103 as being unpatentable over Attie et al. (WO 2016/090077) and Seehra (WO 2018/089715) as applied to claims 7, 27, 146-149, 152, 153, 155-158, 161 and 162 above, and further in view of Lansing et al. (WO2018129397). This rejection is necessitated by Applicant’s amendment. 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 Attie et al. and Seehra and how they meet the limitations of claims 7, 27, 146-149, 152, 153, 155-158, 161 and 162 are outlined above in the preceding rejection and are hereby incorporated. Regarding ActRIIa inhibitors, Seehra teaches an extracellular ActRIIa variant having a sequence with 100% identity to SEQ ID NO: 69 (see claims 109-111 and the Table at p. 27 of Seehra). Seehra also teaches that the Fc domain may be an IgG1 fused to the C-terminus of the ActRIIa polypeptide through a flexible linker such as GGG (see p. 1, lines 25-27; p. 3, lines 18-19; p. 13, lines 12-14; p. 33, lines 27-41 through p. 34, line 1; claim 95). Thus, the combined teachings of Attie et al. and Seehra et al. suggest an ActRIIa inhibitor having the same sequence as instant SEQ ID NO: 69 + the linker GGG + an IgG1 Fc domain.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Attie et al. and Seehra do not teach SEQ ID NOs: 155 and 156 as recited in instant claims 150, 151, 159 and 160. Note that instant SEQ ID NO: 155 encompasses the Fc domain and instant SEQ ID NO: 156 encompasses instant SEQ ID NO: 69 + the linker GGG + instant SEQ ID NO: 155. In addition, as noted above, the combined prior art teachings suggest an ActRIIa inhibitor having the same sequence as instant SEQ ID NO: 69 + the linker GGG + an IgG1 Fc domain, thus, the only element missing from the prior art’s teaching is the sequence of the Fc domain. Lansing et al. teach an Fc domain, SEQ ID NO: 45, sharing 100% sequence identity with instant SEQ ID NO: 155:
Query Match 100.0%; Score 1228; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
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 combined teachings of Attie et al. and Seehra by using the Fc domain taught in Lansing et al. because Lansing et al. teach the Fc domain disclosed therein “unexpectedly feature[s] stronger binding to multiple classes of FCY receptors and enhanced activity of multiple cytotoxicity pathways” and has “enhanced effector function” (see claims 1; 39; p. 70, lines 32-35). The person of ordinary skill in the art would have been motivated to substitute Fc domains because it represents a simple substitution of one known element (an Fc domain) for another to obtain predictable results. The combined prior art of Attie et al. and Seehra taught Fc domains, and Lansing et al. taught an improved Fc domain. Given the teaching of Lansing and colleagues, one having ordinary skill in the art would have recognized that substituting the improved Fc domain would have yielded predictable results and resulted in an improved ActRIIa-Fc product. Furthermore, the person of ordinary skill in the art would be choosing from a finite number of identified, predictable potential Fc domains available in the field of protein engineering. For these reasons, as well, the person having ordinary skill in the art could have reasonably expected success.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 154 and 163 are rejected under 35 U.S.C. 103 as being unpatentable over Attie et al. (WO 2016/090077) and Seehra (WO 2018/089715) as applied to claims 7, 27, 146-149, 152, 153, 155-158, 161 and 162 above, and further in view of Gupta et al. (Journal of Blood Medicine 2010: 1 171-182). This rejection is necessitated by Applicant’s amendment. 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 Attie et al. and Seehra and how they meet the limitations of claims 7, 27, 146-149, 152, 153, 155-158, 161 and 162 are outlined above in a preceding rejection and are hereby incorporated.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Attie et al. and Seehra do not teach the specific subtypes of myelodysplastic syndrome with ring or excess sideroblasts as recited in claims 164 and 163. Gupta et al. review the WHO classifications of MDS-RS, which include, among others, unilineage (i.e., single lineage) and multilineage dysplasia (see p. 172, Table 1). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the conditions taught in Gupta et al. represent sub-categories of MDS-RS because “[m]yelodysplastic syndromes are a spectrum of bone marrow failure disorders that share a common pathologic feature: cytologic dysplasia” (see p. 181, right column, last paragraph). The person of ordinary skill in the art would have been motivated to treat these patients with the ActRIIa-Fc because MDS patients do not response to many conventional treatments. The person of ordinary skill in the art could have reasonably expected success because Attie et al. taught that treatment with ActRIIa-hFc resulted in improvements in hematological parameters in patients with thrombocytopenia and neutropenia (see paragraph [00344]).
Thus, the claims do not contribute anything non-obvious over the prior art.
Response to Arguments
Applicant’s arguments filed 12/18/2025 are acknowledged. The arguments are made in response to now withdrawn rejections.
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.
USP 12,364,737
Claims 7, 27 and 146-163 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,364,737 in view of Wells et al. (CMAJ 2016. DOI:10.1503/cmaj.151077), Seehra (WO 2018/089715) and Lansing et al. (WO2018129397). The claims have been amended to recite treatment of subjects with an ActRIIa variant (SEQ ID NO: 69) who have or at risk of developing thrombocytopenia (claim 7) or neutropenia (claim 27) associated with myelodysplastic syndrome, myelofibrosis or myelofibrosis treatment (claim 7) or associated with a myelodysplastic syndrome or myelofibrosis (claim 27). New claims 146 and 155 recite an Fc domain monomer fused to the C-terminus of the ActRIIa variant by way of a linker, which claim 9 of the reference patent also recites. New claims 147-149 and 156-158 recite the linker is a flexible linker (claims 147, 156), a GGG linker (claims 148, 157) and the Fc domain is a human IgG1 Fc domain (claims 149, 158). New claims 150 and 159 recite the Fc domain comprises the amino acid of SEQ ID NO: 155 and new claims 151 and 160 recite the polypeptide comprises the amino acid sequence of SEQ ID NO: 156. New claims 152 and 161 recite the myelodysplastic syndrome is a very low, low or intermediate risk myelodysplastic syndrome, new claims 153 and 162 recite the myelodysplastic syndrome is myelodysplastic syndrome (lines 5-6), in the alternative and new claims 154 and 163 recite the myelodysplastic syndrome with ring sideroblasts is single lineage dysplasia or multilineage dysplasia or the myelodysplastic syndrome with excess blasts is myelodysplastic syndrome with excess blasts type 1 or myelodysplastic syndrome with excess blasts type 2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent recites methods of administering an extracellular ActRIIa variant to treat anemia associated with a myelodysplastic syndrome or myelofibrosis. The extracellular ActRIIa variant recited in the claims of the reference patent has the sequence set forth in SEQ ID NO: 69 in the alternative, which shares 100% sequence similarity to instant SEQ ID NO: 69. Further, although the claims of the reference patent do not address the risk level of myelodysplastic syndrome, a range of very low to intermediate risk does not introduce a patentable distinction, but rather covers the range of expected disease risk. The differences between the claims are as follows.
First, while the claims of the reference patent recite treating anemia associated with myelodysplastic syndrome or myelofibrosis, the instant claims recite treating thrombocytopenia and neutropenia associated with these same conditions. Nevertheless, the patient populations are overlapping; administering the same agent to treat the same patient population will inherently produce the same effects. The instantly claimed methods are not patentably distinct from those of the reference patent. Further, the art recognized that patients with myelodysplastic syndrome frequently present with anemia, thrombocytopenia or neutropenia (see Wells et al., right column, 1st paragraph).
Second, the claims of the reference patent do not the recite limitations in new claims 147-149 and 156-158. Seehra et al. teach that the linker is a flexible linker and may be GGG and the Fc domain may be an IgG1 (see p. 1, lines 25-27; p. 3, lines 18-19; p. 13, lines 12-14; p. 33, lines 27-41 through p. 34, line 1; claim 95). It would have been obvious to the person of ordinary skill in the art that the flexible linker may be GGG and the Fc domain may be an IgG1 because these are commonly used in the field of Fc variant proteins. The person of ordinary skill in the art would have been motivated to make these substitutions because Seehra teaches the ActRlla variants disclosed therein have “improved properties” such as a greater half-life and solubility (see p. 39, lines 30-35). Given the improved half-life and solubility of the modified soluble extracellular ActRIIa variants taught by Seehra, the person of ordinary skill in the art could have reasonably expected success.
Third, the claims of the reference patent do not teach SEQ ID NOs: 155 and 156 as recited in instant claims 150, 151, 159 and 160. Note that instant SEQ ID NO: 155 encompasses the Fc domain and instant SEQ ID NO: 156 encompasses instant SEQ ID NO: 69 + the linker GGG + instant SEQ ID NO: 155. Seehra teaches an ActRIIa inhibitor having the same sequence as instant SEQ ID NO: 69 + the linker GGG + an IgG1 Fc domain (see p. 1, lines 25-27; p. 3, lines 18-19; p. 13, lines 12-14; p. 33, lines 27-41 through p. 34, line 1; claim 95), therefore, the only thing missing in this teaching is the sequence set forth in instant SEQ ID NO: 155. Lansing et al. teach an Fc domain, SEQ ID NO: 45, sharing 100% sequence identity with instant SEQ ID NO: 155:
Query Match 100.0%; Score 1228; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
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 claims of the reference patent by using the Fc domain taught in Lansing et al. because Lansing et al. teach that this Fc domain “unexpectedly feature[s] stronger binding to multiple classes of FCY receptors and enhanced activity of multiple cytotoxicity pathways” and has “enhanced effector function” (see claims 1; 39; p. 70, lines 32-35). The person of ordinary skill in the art would have been motivated to substitute Fc domains because it represents a simple substitution of one known element (an Fc domain) for another to obtain predictable results. Given the teaching of Lansing and colleagues, one having ordinary skill in the art would have recognized that substituting the improved Fc domain would have yielded predictable results and resulted in an improved ActRIIa-Fc product. Furthermore, the person of ordinary skill in the art would be choosing from a finite number of identified, predictable potential Fc domains available in the field of protein engineering. For these reasons, as well, the person having ordinary skill in the art could have reasonably expected success.
Fourth, the claims of the reference patent do not teach the specific subtypes of myelodysplastic syndrome with ring or excess sideroblasts as recited in claims 164 and 163. Gupta et al. review the WHO classifications of MDS-RS, which include, among others, unilineage (i.e., single lineage) and multilineage dysplasia (see p. 172, Table 1). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the conditions taught in Gupta et al. represent sub-categories of MDS-RS because “[m]yelodysplastic syndromes are a spectrum of bone marrow failure disorders that share a common pathologic feature: cytologic dysplasia” (see p. 181, right column, last paragraph). The person of ordinary skill in the art would have been motivated to treat these patients because MDS patients do not respond to many conventional treatments. The person of ordinary skill in the art could have reasonably expected success because the claims of the reference patent recite treating myelodysplastic patients with ActRIIa-hFc.
In summary, when read in light of the prior art by Wells, Seehra and Gupta et al., the instant claims are not patentably distinct from the claims of the ‘737 patent.
S/N 18/390,085
Claims 7, 27, 146-149, 152, 153, 155-158, 161 and 162 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 92-99 and 102 of copending Application No. in view of 18/390,085 (reference application) in view of Wells and Gupta. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass methods of treating a person having myelodysplastic syndrome, including very low, low or intermediate risk MDS, with an ActRII signaling inhibitor wherein the ActRII signaling inhibitor is a polypeptide comprising an extracellular activin receptor type IIa (ActRIIa) variant and an Fc domain, wherein the polypeptide comprises a GGG linker, and wherein the ActRII signaling inhibitor has the amino acid sequence of SEQ ID NO: 69, which is identical to instant SEQ ID NO: 69.
Further, the claims of the reference application recite the Fc domain is set forth in SEQ ID NO: 79, which shares 100% sequence identity to instant SEQ ID NO: 155 and the polypeptide is set forth in SEQ ID NO: 80, which shares 100% sequence identity to SEQ ID NO: 156. See the following alignment between SEQ ID NO: 80 of the reference application and instant SEQ ID NO: 156. The underlined portion shows the 100% sequence identity between SEQ ID NO: 79 of the reference application and instant SEQ ID NO: 156 (the GGG linker is bolded and italicized):
RESULT 1
US-17-945-324-156
Query Match 100.0%; Score 1871; DB 1; Length 338;
Best Local Similarity 100.0%;
Matches 338; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYATWRNISGSIEIVKKGC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GAILGRSETQECLFYNANWELERTNQTGVERCEGEKDKRLHCYATWRNISGSIEIVKKGC 60
Qy 61 WLDDFNCYDRTDCVETEENPQVYFCCCEGNMCNEKFSYFPEMEVTQPTSGGGDKTHTCPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 WLDDFNCYDRTDCVETEENPQVYFCCCEGNMCNEKFSYFPEMEVTQPTSGGGDKTHTCPP 120
Qy 121 CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK 180
Qy 181 TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV 240
Qy 241 YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS 300
Qy 301 KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 338
||||||||||||||||||||||||||||||||||||||
Db 301 KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 338
From the alignment it is clear that the claims of the reference application encompass the limitations in new claims 147-151 and 156-160.
The differences between the claims are as follows. First, the claims of the reference application recite different but overlapping subpopulations of patients suffering from myelodysplastic syndrome, while the instant claims recite treating thrombocytopenia and neutropenia associated with this same condition. Nevertheless, the goals of the reference claims and the instant claims are the same, namely treating myelodysplastic syndrome. Further, the art recognized that patients with myelodysplastic syndrome frequently present with anemia, thrombocytopenia or neutropenia (see Wells et al., right column, 1st paragraph).
Second, the claims of the reference application do not teach the specific subtypes of myelodysplastic syndrome with ring or excess sideroblasts as recited in claims 164 and 163. Gupta et al. review the WHO classifications of MDS-RS, which include, among others, unilineage (i.e., single lineage) and multilineage dysplasia (see p. 172, Table 1). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the conditions taught in Gupta et al. represent sub-categories of MDS-RS because “[m]yelodysplastic syndromes are a spectrum of bone marrow failure disorders that share a common pathologic feature: cytologic dysplasia” (see p. 181, right column, last paragraph). The person of ordinary skill in the art would have been motivated to treat these patients because MDS patients do not response to many conventional treatments. The person of ordinary skill in the art could have reasonably expected success because the claims of the reference application recite methods of increasing hematopoiesis in this patient population.
In summary, when read in light of the prior art by Wells and Gupta et al., the instant claims are not patentably distinct from the claims of the ‘085 application. This is a provisional nonstatutory double patenting rejection.
S/N 18/443,987
Claims 7, 27, 146-151 and 155-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 18, 23, 24, 27, 32, 35, 41-43, 45 and 48 of copending Application No. 18/443,987 (reference application) of in view of Seehra (WO2018/089715) and Lansing et al. (WO2018129397). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass treating anemia, cytopenia, thrombocytopenia or neutropenia with an extracellular ActRIIa variant. The claims of the reference application are drawn to a method of treating a subject having myelofibrosis comprising the step of administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRIl signaling inhibitor that comprises a sequence having 100% sequence identity to instant SEQ ID NO: 69 in the alternative (i.e., X1 is F; X2 is Y; X3 is E; X4 is L; X5 is E; X6 is R; X7 is R; X8 is E; X9 is E; X10 is K; X11 is D; X12 is K; X13 is R; X14 is L; X15 is Y; X16 is R; X17 is K; X18 is K; X19 is W; X20 is L; X21 is D; X22 is F; X23 is T; X24 is E; X25 is E; X26 is N; and X27 is Q). The instant claims are drawn to the following:
Independent claim 7 - treating a subject having or at risk of developing thrombocytopenia associated with myelodysplastic syndrome, myelofibrosis or myelofibrosis treatment.
Independent claim 27 - treating a subject having or at risk of developing neutropenia associated with myelodysplastic syndrome or myelofibrosis.
The differences between the claims are as follows. First, the claims of the reference application recite different but overlapping subpopulations of patients suffering from myelofibrosis. Nevertheless, the reference claims and the instant claims both encompass treating myelofibrosis, thrombocytopenia or neutropenia (see claim 32 of the reference application).
Second, the claims of the reference patent do not recite limitations in new claims 147-149 and 156-158. Seehra et al. teach that the linker is a flexible linker and may be GGG and the Fc domain may be an IgG1 fused to the C-terminus of the ActRIIa polypeptide (see p. 1, lines 25-27; p. 3, lines 18-19; p. 13, lines 12-14; p. 33, lines 27-41 through p. 34, line 1; claim 95). Thus, the claims of the reference application combined with the teachings of Seehra suggest an ActRIIa inhibitor having the same sequence as instant SEQ ID NO: 69 + the linker GGG + an IgG1 Fc domain.
It would have been obvious to the person of ordinary skill in the art that the flexible linker may be GGG and the Fc domain may be an IgG1 fused at the C-terminus because these are commonly employed modifications in the field of Fc variant proteins. The person of ordinary skill in the art would have been motivated to make these substitutions because Seehra teaches the ActRlla variants disclosed therein have “improved properties” such as a greater half-life and solubility (see p. 39, lines 30-35). Given the improved half-life and solubility of the modified soluble extracellular ActRIIa variants taught by Seehra, the person of ordinary skill in the art could have reasonably expected success.
Third, the claims of the reference application do not teach SEQ ID NOs: 155 and 156 as recited in instant claims 150, 151, 159 and 160. Note that instant SEQ ID NO: 155 encompasses the Fc domain and instant SEQ ID NO: 156 encompasses instant SEQ ID NO: 69 + the linker GGG + instant SEQ ID NO: 155. Lansing et al. teach an Fc domain, SEQ ID NO: 45, sharing 100% sequence identity with instant SEQ ID NO: 155:
Query Match 100.0%; Score 1228; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to use the Fc domain taught in Lansing et al. because they teach the Fc domain disclosed therein “unexpectedly feature[s] stronger binding to multiple classes of FCY receptors and enhanced activity of multiple cytotoxicity pathways” and has “enhanced effector function” (see claims 1; 39; p. 70, lines 32-35). The person of ordinary skill in the art would have been motivated to substitute Fc domains because it represents a simple substitution of one known element (an Fc domain) for another to obtain predictable results. Given the teaching of Lansing and colleagues, one having ordinary skill in the art would have recognized that substituting the improved Fc domain would have yielded predictable results and resulted in an improved ActRIIa-Fc product. Furthermore, the person of ordinary skill in the art would be choosing from a finite number of identified, predictable potential Fc domains available in the field of protein engineering. For these reasons, as well, the person having ordinary skill in the art could have reasonably expected success.
In summary, when read in light of the prior art by Seehra and Lansing et al., the instant claims are not patentably distinct from the claims of the ‘987 application. This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed 12/18/2025 are acknowledged. The arguments are made in response to now withdrawn rejections. Further, since the provisional rejections are not the only remaining rejections, they should not be withdrawn.
Conclusion
No claim is 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 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