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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species of BMP inhibitor which is an ALK2 small molecule inhibitor in the reply filed on 9/8/2026 is acknowledged.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: METHODS OF TREATING LYMPHOPENIA WITH AN ALK2 INHIBITOR AND SUPPLEMENTAL IRON.
Information Disclosure Statement
Reference L, WO 2019/058062 A1, of the IDS filed 6/2/2025 is drawn to a “Thermostatic valve for Motor Vehicle” and appears to be completely unrelated to the instant invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 depends from claim 1, which is drawn to a method for preventing or reducing the development of lymphopenia in a subject undergoing treatment with a BMP inhibitor. Claim 3 recites “the subject has or is at risk of developing a disease or condition that can be treated with a BMP inhibitor.” It reasonably appears the subject of claim 1 is already undergoing treatment with a BMP inhibitor. It is unclear why the subject would be treated if they did not have a disease or condition that can be treated with a BMP inhibitor? Further, generally all humans are “at risk of developing a disease or condition that can be treated with a BMP inhibitor”, making the reference to being “at risk” a meaningless limitation. For these reasons, claim 3 is confusing and indefinite.
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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 75-77, 80-84 and 87-88 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2017/0183411 A1 (Lin, cited in the IDS filed 6/2/2025).
Lin teaches treating a subject having a condition associated with iron deficiency with a BMP antagonist and also with an iron supplement ([0019] and [0120]), i.e., treating a subject undergoing treatment with a BMP inhibitor who is also administered an iron supplement. The BMP antagonist may be administered serially, i.e., before or after, or in combination with an iron supplement ([0120]). BMP inhibitors, the use of which are encompassed in the method taught by Lin, include noggin, “a well-known BMP antagonist”, chordin, ventroptin, Cerberus, gremlin, a dante polypeptide, a DAN polypeptide and a caronte polypeptide ([0082]-[0083], [0136]). The BMP inhibitor may also be a hemojuvelin (HJV) inhibitor, e.g., a soluble HJV polypeptide fused to an Fc ([0083]). It reasonably appears absent evidence to the contrary that the method of Lin would treat or reduce the development of lymphopenia.
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.
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.
Claim(s) 1-3, 75-88 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0183411 A1 (Lin, cited in the IDS filed 6/2/2025) as applied to claims 1-3, 75-77, 80-84 and 87-88 above, and further in view of Abdelmahumad et al. (Case Rep. Oncol. 13:793-797, July 2020, cited in the IDS filed 6/2/2025), Abuirmeilch et al. (Int. J. Clin. Pharm. 36:264-267, 2014), Assholf et al. (Blood, 129(13): 1823-1830, 2017, cited in the IDS filed 6/2/2025), Peterson et al. (7th Congress Int. BioIron Soc. (IBIS) Biennial World Meeting, Poster #102, May 7-11, 2017) and Ganz, T. (N. Engl. J. Med. 381:1148-1157, Sept. 2019).
Lin teaches treating a subject having a condition associated with iron deficiency with a BMP antagonist and also with an iron supplement ([0019] and [0120]), i.e., treating a subject undergoing treatment with a BMP inhibitor who is also administered an iron supplement. The BMP antagonist may be administered serially, i.e., before or after, or in combination with an iron supplement ([0120]). BMP inhibitors, the use of which are encompassed in the method taught by Lin, include noggin, “a well-known BMP antagonist”, chordin, ventroptin, Cerberus, gremlin, a dante polypeptide, a DAN polypeptide and a caronte polypeptide ([0082]-[0083], [0136]). The BMP inhibitor may also be a hemojuvelin (HJV) inhibitor, e.g., a soluble HJV polypeptide fused to an Fc ([0083]). Lin does not teach wherein the iron supplement is administered orally or intravenously or an ALK2 inhibitor (the elected species of BMP inhibitor).
Abdelmahumad et al. teaches that iron deficiency anemia (IDA) is the most common type of anemia and may present with lymphocytopenia (start of Abstract and p. 794, second paragraph, and p. 796, fourth paragraph). In a case study of a 17-year-old female, treatment of severe anemia and lymphocytopenia with intravenous ferric carboxymaltose treated the anemia and lymphocytopenia (p. 794, last paragraph, and 795, first paragraph).
Abuirmeilch et al. teaches a clinical case in which a woman known to have iron deficiency anemia (IDA) also had persistent and chronic leukopenia, expressing more specifically as neutropenia, for many years (p. 264, col. 2, third paragraph, and paragraph bridging pp. 264-265). When she adhered to a treatment regimen of oral iron supplements twice a day for 2.5 months, both her IDA and neutropenia were treated (p. 265, col. 2, second and third paragraphs). After reviewing the long-term data for the patient, it was concluded (paragraph bridging pp. 266-267) the significant improvement in the neutropenia “after correcting her iron store status lead us to believe that the treatment of the chronic iron deficiency anemia with oral iron supplements also treated her 16 yearlong documented chronic idiopathic neutropenia.” Further, a study is noted in which 2.1% of adults having incidental neutropenia also had IDA, and treatment with iron supplementation improved neutrophil count (p. 267, col.1, second paragraph). They suggest the existence of iron deficiency-induced neutropenia and treatment thereof with iron supplemental therapy (p. 267, third paragraph).
Assholf et al. teaches hepcidin reduces intestinal iron absorption and iron export from monocytes/macrophages, thus elevated serum hepcidin levels enhance iron storage and reduce iron availability and iron-restricted erythropoiesis, leading to severe functional iron deficiency anemia and anemia of chronic disease (ACD) (p. 1823, col. 1, first paragraph). Bone morphogenic protein (BMP) activation leads to hepcidin transcription, but it has been shown that liver-specific deletion of BMP receptor ALK2 (ACVR1) or ALK3 blocks downstream hepcidin production and results in iron overload in mice (p. 1823, paragraph bridging cols. 1-2). Assholf et al. showed that momelotinib (MMB), a small molecule JAK1/JAK2 and ALK2 inhibitor, reduced iron availability that decreases hepcidin production and ameliorated anemia of chronic disease in rats and increased the amount of circulating iron, but it also reduced the number of white blood cells and neutrophils (p. 1825, col. 1, second and third paragraphs). In a phase 2 clinical trial for MMB treatment of myelofibrosis (MF), which is often accompanied by the development of anemia and elevated serum hepcidin levels (p. 1823, col. 2, second paragraph), patients became transfusion-independent (p. 1825, last paragraph). It is concluded (p. 1830, col. 1, first paragraph), “Our results provide evidence of a direct role of MMB in regulating iron homeostasis and suggest a therapeutic rationale for MMB treatment in patients with ACD.”
Peterson et al. teaches selective small molecule ALK2 inhibitor, TP-0184. It had “robust in vitro and in vivo activity… in multiple models.” In both a mouse model of anemia of chronic disease (ACD) induced by turpentine oil-mediated stimulation or by TC-1 cancer cells reduced induction of hepcidin. In a heat-killed Brucella abortus (HKBA) mouse model of ACD, TP-0184 reduced HKBA-mediated hemoglobin loss. It was concluded, “Taken together, our data support the targeting of ALK2 as a potential approach for the inhibition of ACD, as well as the development of TP-0184 as a therapeutic option for patients with ACD.”
Ganz discusses cause and treatment of anemia of inflammation, which has differences with iron deficiency (Table 1), such as low serum hepcidin in iron deficiency and high levels in anemia of inflammation. It is noted that absorption of oral iron is often impaired in diseases with moderate to severer systemic inflammation. However, intravenous iron is relatively safe and can be very effective (p. 1153, col. 1, last paragraph). “New compounds for the specific treatment of anemia of inflammation are under development. The targeted mechanisms are designed to reverse hypoferremia in anemia of inflammation by decreasing the level of hepcidin with the use of hepcidin binders or by hindering the access of hepcidin to its target ferroportin or antagonizing the signaling pathways that stimulate hepcidin production during inflammation (Table 2).” (p. 1154, col. 2, third paragraph) These include BMP, hepcidin and HJN antibodies, the ACVR1/AKL2 and JAK1/2 inhibitor momelotinib, and ACVR1/ALK2 inhibitor TP0-0184, most of which are in clinical trials (Table 2). High levels of circulating hepcidin decrease iron release from spleen and liver (p. 1151, col. 2).
It would have been obvious wherein the patient being treated for anemia, e.g., IDA or ACD, also had leukopenia because Abuirmeilch et al. and Abdelmahumad et al. taught that IDA may be accompanied by leukopenia. Both taught that treatment with iron, oral or intraveneous, could treat the leukopenia as well as the anemia. Also, Assholf et al. showed that treatment of a rat model of ACD with MMB led to reduced white blood cell and neutrophil counts. It would have further been obvious to treat the anemia with a BMP inhibitor, including a hepcidin or ALK2 inhibitor, e.g., TP-0184 or momelotinib, because Ganz taught these agents were in clinical trials for treatment of anemia of inflammation and Assholf et al. taught momelotinib showed activity also for treatment of ACD in a rodent model and amelioration of anemia in MF patients. Additionally, Peterson et al. showed in three different mouse anemia models that TP-1084 reduced hepcidin induction or hemoglobin loss. Both Assholf et al. and Peterson et al. suggest treatment of anemia with an ALK2 inhibitor. However, because these agents also release iron into circulation from stores (e.g., Assholf et al. and Ganz), it would have been obvious to additionally treat with supplemental iron to replenish the stored iron that was released and also to treat leukopenia if present. It would have been obvious wherein the iron was administered orally or by intravenous infusion (e.g., Ganz) and soon before, concurrently with or after the BMP-related anemia treatment.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US Patent 8,841,431 B2 (cited in the IDS filed 6/2/2025) teaches conditions with elevated hepcidin levels, such as cancer, and the treatment thereof with a hepcidin modulating antibody or BMP modulator, which may be used in combination with a medicament for treating anemia, such as an iron supplement (col. 26, lines 21-58). As claimed, a disclosed nucleic acid that binds hepcidin may be the hepcidin inhibitor (claims 1-3). This reference is cumulative with those relied on above for teaching administration of a BMP inhibitor with an iron supplement.
Wong et al. (Int. J. Blood Res. Disord. 11(1):096, 7 pages, 2024, p. 4, col. 2, second paragraph), teach “Receiving intravenous iron optimisation significantly increased the post-infusion Hb, iron saturations, and ferritin levels as expected (all p < 0.001). There was no significant difference found in WCC and neutrophil count post-iron infusion. There was a statistically significant difference in lymphocyte and monocyte count post-iron infusion, although the absolute difference was clinically small (Table 5).” (see also p. 6, col. 2, third paragraph) A substantial link between IDA and leukopenia and neutropenia was found, even though a direct dose-response relationship between the supplemental iron and amelioration of the neutropenia and/or leukopenia was not; although, study-associated reasons why this may have been the case is discussed (p. 7, col. 1, second and third paragraphs). Wong et al. also note that ethnicity appears to be a significant factor in response (e.g.., p. 6, col. 1, second paragraph).
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
April 22, 2026
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