DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Application
The claims and remarks of 14 August 2025 are entered.
Claims 2, 3, 7-10, and 18 have been canceled. Claims 1, 4-6, and 11-17 are pending and are being examined on the merits.
The rejections under 35 U.S.C. 103 are maintained, with the Examiner’s response found below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
1. Claims 1, 5, and 11-15 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sherman et al. (US 2010/0028332 A1, published 4 February 2010, hereafter referred to as ‘332), Seehra et al. (WO 2010/019261 A1, published 18 February 2010, hereafter referred to as ‘261), and Mesa et al. (Leukemia Research 33:1199-1203, hereafter referred to as Mesa).
The ‘332 application discloses activin and ActRIIba antagonists (see e.g. [0008]). ‘332 also discloses that ActRIIb antagonists can increase RBC and hemoglobin levels (see e.g. [0008]). The ‘332 application discloses treatment of anemia using the ActRIIb antagonists, including anemia associated with myelofibrosis (see e.g. [0014]-[0015]).
The difference between ‘332 and the claimed invention is that while ‘332 discloses treatment of anemia associated with myelofibrosis, it does not disclose SEQ ID NO: 28 or treatment of one or more of splenomegaly, iron overload, erythroblast-induced bone pathology, and/or bone marrow hypercellularity as claimed.
The ‘261 application discloses a method of administering GDF Traps to increase red blood cell and hemoglobin levels, where the GDF Traps comprise variant ActRIIB polypeptides (see e.g. p.2 lines 28-31, p.3 lines 1-6, claim 1). The methods are disclosed as those that “treat disorders associated with low red blood cell or hemoglobin levels in patients in need thereof” as well as anemia (see e.g. p.3 lines 4-6 and p.17 lines 3-6). The GDF Traps are disclosed as comprising residues 21-29 up to residues 109-134 of SEQ ID NO: 1 or SEQ ID NO: 39 (see e.g. p.6 lines 23-29). The ‘261 art also discloses that ActRIIB variant proteins beginning at amino acid 29 is expected to retain ligand binding activity and the active region comprises residues 29-109 of SEQ ID NO: 1 (see e.g. p.24 lines 13-14, 23-24, claims 1 and 3). It is also disclosed that position 79 is of particular importance and that a L79E or L79D mutation retains binding to GDF-11 while having greatly reduced activin binding resulting in increases in RBCs but lowered effects on other types of tissues (see e.g. p.27 lines 8-18, claim 1). ‘261 discloses that GDF Trap polypeptides can be used in particular patient populations, including those suffering from anemia as a result of thalassemias (see e.g. p.45 lines 15-16 and 28). An exemplary form is disclosed in SEQ ID NO: 28 containing the L79D, residues 25-131, a and a Fc without a leader sequence (see e.g. Figure 7, claim 7). Finally, ‘261 discloses that in iron-deficient anemia the administration of RBCs via transfusions can be combined with administration of GDF Trap polypeptides (see e.g. p.47 line 32 to p.48 line 4).
Mesa discloses co-morbidity of symptomatic splenomegaly with 76% of primary myelofibrosis patients (see e.g. Table 1). Mesa’s disclosure reasonably leads one of ordinary skill to expect that a patient with myelofibrosis would also have symptomatic splenomegaly. As discussed above, the ‘332 art already discloses co-morbidity of anemia with myelofibrosis patients.
It would have been obvious to one of ordinary skill at the time of invention to combine the treatment of anemia associated with myelofibrosis of ‘332 by utilizing the GDF Trap polypeptide of ‘261, including SEQ ID NO: 28. Furthermore, based upon the disclosure of Mesa one of ordinary skill in the art would expect the subject being treated for anemia associated with myelofibrosis to also have symptomatic splenomegaly, and in treatment of the underlying anemia expect the splenomegaly to also be treated. The rationale comes from ‘332 already disclosing the usefulness of ActRIIb antagonists for treatment of anemia associated with myelofibrosis, and in doing so treat the underlying myelofibrosis by utilizing the GDF Traps of ‘261. There would have been a reasonable expectation of success because the particular polypeptide as claimed is disclosed by ‘261 as being particularly useful and ‘332 discloses those family of peptides can treat anemias associated with myelofibrosis, such that one of ordinary skill in the art would have expected treatment of the underlying anemia to also treat the resultant myelofibrosis. Since symptomatic splenomegaly is also associated with myelofibrotic anemia one would also have a reasonable expectation that treatment of the anemia would also treat the splenomegaly since it is a consequence of the anemia. The invention would have been prima facie obvious to one of ordinary skill in the art at the time of invention.
With respect to claims 11-13, the polypeptide of ‘261 satisfies the identity requirements of the claims.
With respect to claims 14 and 15, as set forth above ‘261 discloses administration of RBCs via transfusion in combination with GDF Trap polypeptide administration.
2. Claims 4-6, 16, and 17 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sherman et al. (US 2010/00028332 A1, published 4 February 2010), Seehra et al. (WO 2010/019261 A1, published 18 February 2010), and Mesa et al. (Leukemia Research 33:1199-1203) as applied to claim 1 above, and further in view of Di Tucci et al. (Eur. J. Haematology 78:540-542, published February 2007, hereafter referred to as Di Tucci) and Georgiades et al. (Am. J. Radiol. 179:1239-1243, published November 2002, hereafter referred to as Georgiades).
The relevance of ‘332, ‘261, and Mesa is set forth above. The difference between the prior art references and the claimed invention is that none disclose the additional symptoms suffered by the patient or administration of iron chelating agents.
Di Tucci discloses iron overloading in liver and marrow due to transfusion in a patient with myelofibrosis as well as treatment of overloading via chelation therapy using deferasirox (see e.g. Abstract, Table 1).
Georgiades discloses that in myelofibrosis extramedullary blood formation is a routine occurrence when primary sites of hematopoiesis fail, generally targeting the livers, spleen, and paraspinal regions of the thorax (see e.g. p.1239). The failure of hematopoiesis in the marrow is a bone pathology, Georgiades also mentions rib expansion as routine manifestations, i.e. another form of bone pathology (see e.g. p.1239). Since normal hematopoiesis require properly formed erythroblasts, the bone pathology in the marrow of Georgiades can reasonably be considered an erythroblast-induced pathology.
It would have been obvious to one of ordinary skill in the art at the time of invention that the method of ‘332, ’261, and Mesa could have been modified to include myelofibrosis patients suffering from tissue iron overloading, extramedullary erythropoiesis, or erythroblast-induced bone pathology as discussed in Di Tucci or Georgiades. The rationale comes from Di Tucci or Georgiades describing patients with myelofibrosis such that one of ordinary skill in the art would consider such patients part of the population encompassed by ‘332, ‘261, and Mesa. There would have been a reasonable expectation of success because the claims merely require that the patients have the claimed conditions, i.e. there is no requirement that those conditions actually be treated. The invention would have been prima facie obvious to one of ordinary skill in the art at the time of invention.
With respect to claims 16 and 17, as discussed above the Di Tucci art indicates that chelation therapy with deferasirox can be very effective, and accordingly one of ordinary skill in the art would consider combining with the GDF Trap of ‘332 and ‘261.
Response to Arguments (both rejections):
The Applicants summarize the rejection of record.
The Examiner finds no issues with the summary as provided.
The Applicants argue claim 1 requires administration treat one or more of splenomegaly, iron overload, erythroblast-induced bone pathology, and/or bone marrow hypercellularity. The Applicants argue the Examiner has not showing any teaching or suggestion from the prior art for treatment of the claimed conditions. The Applicants argue no references explicitly refer to treating myelofibrosis or the significant technical effects provided by the claimed method. The Applicants argue mere reference to elements of the claim is insufficient and that the prior art must present a reason to combine.
The Examiner does not dispute the limitations of the claim, as they were previously addressed in the rejection of record. The Examiner disagrees that a rationale to combine is lacking. The polypeptide was established in the prior art for treatment of anemia in myelofibrosis patients. Those patients are also known in the art to frequently suffer from splenomegaly due to their underlying anemia. It reasonably follows that treatment of the anemia in myelofibrosis patients therefore also treats splenomegaly. The rejection is not merely based upon recognition of elements from disparate references and no rationale to utilize the art of record, but rather recognition of the benefits of the claimed polypeptide on anemia in myelofibrosis patients, which reasonably follows to splenomegaly treatment. As to significant technical effects, that is not a secondary consideration that is relevant to obviousness.
The Applicants argue the instant application shows GDF traps can provide unexpected benefits in disorders of ineffective erythropoiesis. The Applicants point to Example 22. The Applicants argue the model shows treatment of splenomegaly and bone mineral density. The Applicants argue improved iron homeostasis. The Applicants argue the GDF traps reduced multiple indicators of iron overload in Figure 31.
The Examiner disagrees that the benefits as disclosed are commensurate in scope with the claims. Nothing in Example 22 or Figure 31 refers to treatment of myelofibrosis. The mouse model is one of ineffective erythropoiesis due to β-thalassemia, which is distinct from myelofibrosis. As the Applicants would not submit to a rejection over a prior art reference disclosing only treatment of β-thalassemia with a GDF trap, the Examiner does not accept those results as establishing unexpected results in treatment of myelofibrosis.
The Applicants argue GDF traps have a beneficial effect on expression of hepcidin, referring to Figure 33.
Again, the Applicants are arguing limitations that are not claimed. Nothing in the pending claims discusses or refers to increasing expression of hepcidin. Even considering that feature, again Figure 33 refers to such results in a model of β-thalassemia, not myelofibrosis. As argued above, the Examiner does not find that the models are equivalent to each other.
The Applicants argue the specification establishes that the method can treat myelofibrosis and associated disorders. The Applicants argue disorders of ineffective erythropoiesis includes myelofibrosis, and the term represents a group of erythroid disorders in which erythrocyte production is decreased despite an increase in earlier stages of erythropoiesis. The Applicants refer to the above technical results as demonstrating the method produces beneficial changes in endpoints of major complications of ineffective erythropoiesis, referring again to Example 22. The Applicants argue in contrast to existing therapies, the GDF trap polypeptides reduce iron overloading in murine models while increasing RBC levels, thereby distinguishing from the standard of care in transfusion medicine.
The Examiner disagrees. The models of the specification again do not actually consider any subjects or animals with myelofibrosis. The Examples to which the Applicants refer to are those where a model of β-thalassemia is utilized, which the Examiner does not concede as being equivalent to a model of myelofibrosis. The Examiner does not dispute the definition of ineffective erythropoiesis, but the claims are directed to this generic condition but rather to specific patients with myelofibrosis. As to the technical effects, as discussed above the Examiner has considered those arguments and found them unpersuasive. The Examiner does not dispute that the GDF traps represent a difference in care as compared to blood transfusions, but those features are not claim limitations outside of supplemental therapy as in claims 14 and 15.
The Applicants argue the above technical effects were confirmed in a phase 2 trial as provided in Blood Advances 8:4511-4522, 2024. The Applicants argue this showed luspatercept administration to myelofibrosis patients via s.c. injection. The Applicants discuss the patient cohorts for treatment and primary endpoints to be analyzed. The Applicants argue a 50% or greater reduction in MPN-SAF TSS score across all cohorts when treated in accordance with the claims.
The Examiner argues that post-filing art cannot establish secondary considerations that would overcome a rejection for obviousness. The Geld art certainly shows the utility of luspatercept administration. However, post-effective-filing-date evidence offered to illuminate the post-effective-filing-date state of the art is improper. Amgen, 872 F.3d at 1374, 124 USPQ2d at 1359. Geld may establish treatment of myelofibrosis patients in accordance with the claimed methods, however the problem remains that the specification does not disclose or suggest those same methods that might overcome the conclusion of obviousness through secondary considerations.
The Applicants reiterate that the claimed references do not explicitly refer to the claimed method or its technical effects. The Applicants summarize the other arguments presented above.
The Examiner disagrees for the reasons as found above.
The Applicants’ arguments have been considered but are not persuasive. The rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/Z.J.M/Patent Examiner, Art Unit 1658 /SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658