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 .
Claim Status
Claims 6-17, 19-22, 25-26, 28-31, 33-34, 36-40, 44, 46-47, and 49-52 are cancelled. Claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a continuation of PCT/US22/40920 (filed on 08/19/2022) which claims benefit of Provisional U.S. Applications No. 63/235,096 (filed on 08/19/2021), 63/287,823 (filed on 12/09/2021), 63/350,706 (filed on 06/09/2022), and 63/354,158 (filed on 06/21/2022). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 have an effective filing date of 08/19/2021 corresponding to Provisional U.S. Application No. 63/235,096.
Information Disclosure Statement
The information disclosure statement(s) filed on 06/05/2025 has/have been considered. Signed copies are enclosed.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35 and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 35 is drawn to a method of treating a subject having myelofibrosis comprising administering in combination a cytopenia-associated myelofibrosis treatment and an ActRIl signaling inhibitor “wherein the ActRIl signaling inhibitor is an activin A antibody or an antigen binding fragment thereof, a myostatin antibody or an antigen binding fragment thereof, an ActRIl antibody or an antigen binding fragment thereof, an activin B antibody or an antigen binding fragment thereof, or a GDF-11 antibody or an antigen binding fragment thereof” (lines 1-4). This claim language reads on a large number of antigen binding fragments of the aforementioned antibodies. It is unclear what portions (i.e. an antigen binding fragment) of an activin A, myostatin, ActRIl, activin B, and GDF-11 antibodies retain the abilities to bind activin A, myostatin, ActRIl, activin B, and GDF-11 respectively.
Claim 43 is drawn to the method wherein the ActRII signaling inhibitor is an ActRIIA ligand trap that comprises “a polypeptide comprising an extracellular activin receptor type Ila (ActRlla) variant, the variant having a sequence of [SEQ ID NO: 1]... and wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRlla having the sequence of SEQ ID NO: 73” (lines 1-12). SEQ ID NO: 1 recites 27 variable amino acid residues, delineating 2-9 alternative amino acids for each variable amino acid residue, leading to a large number of possible ActRlla variants. While claim 43 requires at least one amino acid substitution relative to SEQ ID NO: 73, it does not otherwise limit the number of substitutions or combinations of substitutions.
The instant specification states “[t]he term ‘antibody’ is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity” (¶ 0083) and “’[a]ntibody fragments’ include a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody” (¶ 0084). These definitions include multiple types of antibodies and antigen binding fragments thereof, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions. For example, Sifniotis et al. state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019, Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4) . These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). The term “antibody,” therefore, encompasses a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody or antigen binding fragment thereof binds activin A, myostatin, ActRIl, activin B, and GDF-11 is not a sufficient description.
Furthermore, the instant specification does not specified how to create antigen binding fragments that exhibit the desired biological activity (i.e. retain the ability to bind said antigen) nor the minimal number of CDRs required (i.e. the antigen binding fragment can contain less than 6 CDRs).
The instant specification discloses exemplary activin A antibodies in Tables 1-2 (Table 1 shows HCVR and LCVR; Table 2 shows HCDR1-3 and LCDR1-3). The instant specification discloses exemplary myostatin antibodies in Tables 3 and 5-7 (Table 3 shows HCVR and LCVR; Table 5 shows HCDR1-3; Table 6 shows LCDR1-3; Table 7 shows heavy and light chains). The instant specification discloses exemplary ActRII antibodies in Tables 8-10 (Table 8 shows HCVR and LCVR; Table 9 shows HCDR1-3 and LCDR1-3; Table 10 shows heavy and light chains). The instant specification discloses an activin B antibody comprising SEQ ID NOs: 494-495 for the HCVR and LCVR respectively (¶ 0149). These antibodies are full-length and contain a minimum of 6 CDRs.
The instant specification does not give examples of GDF-11 antibodies and instead relies on the prior art. Prior art does teach GDF-11 antibodies such as those Jiao et al. (GDF11 replenishment protects against hypoxia-mediated apoptosis in cardiomyocytes by regulating autophagy, European Journal of Pharmacology, Volume 885, 2020, Pg. 1-10; Pg. 1, Abstract, lines 10-11, “Antibody against GDF11 [anti-GDF11] was used to inhibit the function of GDF11”). Jiao et al., however, does not teach fragments of the anti-GDF-11 antibody retain binding to GDF-11.
The instant specification teaches in Example 10 that “an ActRIIA ligand trap containing an extracellular ActRIIA variant (e.g., an extracellular ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72))” (¶ 0259). Note that SEQ ID NOs: 1-5 contain variable amino acid resides and are provided to describe SEQ ID NOs: 6-72. Therefore, the instant specification teaches the ActRIIA variants comprising sequences with no variable amino acid residues in SEQ ID NOs: 6-72.
Thus, as instantly claimed, the claims read on a genus of antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35) and a genus of ActRIIA variants comprising numerous substitutions (claim 43).
The instant specification contemplates antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35) and ActRIIA variants comprising numerous substitutions (claim 43). However, the instant specification does not teach that these antigen binding fragments and ActRIIA variants are tested and retain their correlated functions. There is insufficient evidence of possession of invention regarding structure of all antigen binding fragments (claim 35) and all ActRIIA variants (claim 43) as claimed.
Regarding claim 35, the antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 can comprise less than 6 CDRs. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen binding region of the antibody, i.e. anywhere in the VH and VL, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicate CDRs are extremely sensitive to perturbation and cannot be mutated or changed, applicable to deleting portions of CDRs, predictably.
Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding.
Regarding claim 43, the ActRlla variants can comprise a large number of substitutions or combinations of substitutions. However, not all variants retain in vivo activity. For example, US20190345225A1 (filed 2017-11-09, published 2019-11-14; IDS filed 06/05/2025, Cite No. DM; hereinafter referred to as US ‘225) states “[f]or example, an ActRIIA variant having the sequence [SEQ ID NO: 150]... has reduced activity in vivo, indicating that the substitution of alanine (A) for lysine (K) at X17 is not tolerated. ActRIIA variants of the invention... therefore, retain amino acid K at position X17” (¶ 0116). Claim 43 specifies "X17 is K, A, Y, F, or I" (line 9). As instant SEQ ID NOs: 6-72 include retain amino acid K at position X17, it is not shown that ActRIIA variants wherein X17 is A, Y, F, or I retain in vivo activity in the instant specification.
Applicant is claiming a large and structurally diverse genus of antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35) and genus of ActRIIA variants comprising numerous substitutions (claim 43). Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genera claimed, specifically (i) which antigen binding fragments of the activin A, myostatin, activin B, and GDF-11 antibodies retain the ability to bind said antigen and the minimal number of CDRs required (e.g. the antigen binding fragment can contain less than 6 CDRs) and (ii) which ActRIIA variants (e.g. which substitutions or combinations of substitutions) retain their in vivo activity.
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed antigen binding fragments and ActRIIA variants. Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information in the broadly claimed genera. The specification does not provide specific or detailed structural characteristics of (i) antigen binding fragments of activin A, myostatin, activin B, and GDF-11 antibodies comprising less than 6 CDRs nor (ii) ActRIIA variants comprising all substitutions or combinations of substitutions as recited in claims 35 and 43. It is not clear if all antigen binding fragments and all ActRIIA variants retain their functions. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided: The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the “written description” inquiry, whatever is now claimed.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these antigen binding fragments and ActRIIA variants could perform the same functions (i.e. binding to activin A, myostatin, activin B, or GDF-11 for the antigen binding fragments and binding to ligands for ActRIIA variants) as the antigen binding fragments and ActRIIA variants recited in claims 35 and 43. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genera of antigen binding fragments and ActRIIA variants having the same functions based on the limited examples given in the instant specification.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure(s) and functional attribute(s) of the encompassed genera of antigen binding fragments and ActRIIA variants as claimed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only (i) activin A, myostatin, activin B, and GDF-11 antibodies comprising 6 CDRs as stated in the instant specification or prior art and (ii) ActRIIA variants comprising SEQ ID NOs: 6-72 as stated in the instant specification, but not the full breadth of the claims, meet the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of claims 35 and 43. Claims 35 and 43 fail to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
Claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of ActRIIA/B-mFc and ruxolitinib, does not reasonably provide enablement for a method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (2) the state of the prior art
Claim 1 is drawn to "[a] method of treating a subject having myelofibrosis, the method comprising the step of administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRII signaling inhibitor" (lines 1-3).
Claim 5 is drawn to "[a] method of treating a cytopenia in a subject diagnosed as having myelofibrosis, the method comprising the step of administering in combination to the subject an effective amount of a cytopenia- associated myelofibrosis treatment and an ActRIl signaling inhibitor" (lines 1-3).
Claim 35 is drawn to a method of treating a subject having myelofibrosis comprising administering in combination a cytopenia-associated myelofibrosis treatment and an ActRIl signaling inhibitor “wherein the ActRIl signaling inhibitor is an activin A antibody or an antigen binding fragment thereof, a myostatin antibody or an antigen binding fragment thereof, an ActRIl antibody or an antigen binding fragment thereof, an activin B antibody or an antigen binding fragment thereof, or a GDF-11 antibody or an antigen binding fragment thereof” (lines 1-4). This claim language reads on a large number of antigen binding fragments of the aforementioned antibodies. It is unclear what portions (i.e. an antigen binding fragment) of an activin A, myostatin, ActRIl, activin B, and GDF-11 antibodies retain the abilities to bind activin A, myostatin, ActRIl, activin B, and GDF-11 respectively.
Claim 43 is drawn to a method of treating a subject having myelofibrosis comprising administering in combination a cytopenia-associated myelofibrosis treatment and an ActRIl signaling inhibitor wherein the ActRII signaling inhibitor is an ActRIIA ligand trap that comprises “a polypeptide comprising an extracellular activin receptor type Ila (ActRlla) variant, the variant having a sequence of [SEQ ID NO: 1]... and wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRlla having the sequence of SEQ ID NO: 73” (lines 1-12). SEQ ID NO: 1 recites 27 variable amino acid residues, delineating 2-9 alternative amino acids for each variable amino acid residue, leading to a large number of possible ActRlla variants. While claim 43 requires at least one amino acid substitution relative to SEQ ID NO: 73, it does not otherwise limit the number of substitutions or combinations of substitutions.
The instant specification states "the term 'cytopenia-associated myelofibrosis treatment' refers to a drug that is either approved for the treatment of myelofibrosis or that is in clinical development for the treatment of myelofibrosis and that has as an adverse reaction the development of a cytopenia (e.g., anemia, thrombocytopenia, or neutropenia)" (¶ 0088) and "ActRII signaling inhibitor can be an antibody that binds to an ActRII ligand, an anti-ActRII antibody, or an ActRII ligand trap" (¶ 0004).
The field of invention resides in the fields of chemistry and biology, specifically clinical medicine, highly complex and unpredictable arts. Although claims 1 and 5 broadly recite a method of treating a subject having myelofibrosis (claim 1) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRII signaling inhibitor, the dependent claims demonstrate that practicing the claimed invention encompasses numerous variables.
For example, dependent claims recite when the cytopenia-associated myelofibrosis treatment and ActRII signaling inhibitor are administered in the course of treatment (claims 2-4), effect of treatment (claim 18), disease criteria (claims 23-24 and 32), specific cytopenia-associated myelofibrosis treatments (claim 27), and specific ActRII signaling inhibitors (claims 35, 41-43, 45, and 48).
Collectively, the dependent claims demonstrate that the invention is directed to methods of treating a subject having myelofibrosis (claim 1) or cytopenia in a subject having myelofibrosis (claim 5), subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on the manifestation of the disease in the subject, the specific cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors administered, and when said medications are administered.
Cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors are not defined by a specific type of molecule. The following describes different types of cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors and their uses in treatment:
Cytopenia-associated myelofibrosis treatments
US20180050085A1 (filed 2017-07-26, 2018-02-22 published; hereinafter referred to as US '085) states "Hydroxycarbamide (hydroxyurea, HC) is the most commonly used… However, HC can often exacerbate cytopenias and therefore is often not well tolerated" (¶ 0240) and "JAK inhibitors have little to no effect on many manifestations (complications) of the disease [myelofibrosis] including, for example, cytopenia… Moreover, JAK inhibitors have been shown to induce, or worsen, thrombocytopenia, anemia, and neutropenia in some patients" (¶ 0003). Jak inhibitors include a variety of medications such as "ruxolitinib, fedratinib (SAR302503), monoelotinib (CYT387), pacritinib, lestaurtinib, AZD-1480, BMS-911543, NS-018, LY2784544, SEP-701, XL019, and AT-9283" (US '085, ¶ 0006). This teaching indicates cytopenia-associated myelofibrosis treatments include distinct classes of molecules (e.g. HC and Jak inhibitors) with different adverse effects in patients (e.g. general cytopenia or, more specifically, thrombocytopenia, anemia, and neutropenia).
ActRII signaling inhibitors
Antagonistic antibodies: The instant specification states “[t]he term ‘antibody’ is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity” (¶ 0083) and “’[a]ntibody fragments’ include a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody” (¶ 0084). These definitions include multiple types of antibodies and antigen binding fragments thereof, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions. For example, Sifniotis et al. state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019, Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4) . These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). The term “antibody,” therefore, encompasses a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody or antigen binding fragment thereof binds activin A, myostatin, ActRIl, activin B, and GDF-11 is not a sufficient description.
Furthermore, the instant specification does not specified how to create antigen binding fragments that exhibit the desired biological activity (i.e. retain the ability to bind said antigen) nor the minimal number of CDRs required (i.e. the antigen binding fragment can contain less than 6 CDRs).
The instant specification discloses exemplary activin A antibodies in Tables 1-2 (Table 1 shows HCVR and LCVR; Table 2 shows HCDR1-3 and LCDR1-3). The instant specification discloses exemplary myostatin antibodies in Tables 3 and 5-7 (Table 3 shows HCVR and LCVR; Table 5 shows HCDR1-3; Table 6 shows LCDR1-3; Table 7 shows heavy and light chains). The instant specification discloses exemplary ActRII antibodies in Tables 8-10 (Table 8 shows HCVR and LCVR; Table 9 shows HCDR1-3 and LCDR1-3; Table 10 shows heavy and light chains). The instant specification discloses an activin B antibody comprising SEQ ID NOs: 494-495 for the HCVR and LCVR respectively (¶ 0149). These antibodies are full-length and contain a minimum of 6 CDRs.
The instant specification does not give examples of GDF-11 antibodies and instead relies on the prior art. Prior art does teach GDF-11 antibodies such as those Jiao et al. (GDF11 replenishment protects against hypoxia-mediated apoptosis in cardiomyocytes by regulating autophagy, European Journal of Pharmacology, Volume 885, 2020, Pg. 1-10; Pg. 1, Abstract, lines 10-11, “Antibody against GDF11 [anti-GDF11] was used to inhibit the function of GDF11”). Jiao et al., however, does not teach fragments of the anti-GDF-11 antibody retain binding to GDF-11.
Applicant is claiming a large and structurally diverse genus of antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35). Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which antigen binding fragments of the activin A, myostatin, activin B, and GDF-11 antibodies retain the ability to bind said antigen and the minimal number of CDRs required (e.g. the antigen binding fragment can contain less than 6 CDRs).
Ligand traps: US '085 states numerous ligands of ActRII can be targeted via ligand traps to inhibit ActRII signalling including "BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF-β1, TGF-β2, TGF-β3, activin A, activin B, activin C, activin E, activin AB, activin AC, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin, MIS, and Lefty" (¶ 0108). GDF ligand traps were tested and had a range of affinities to ActRII ligands in US '085 (Example 5, ¶ 0312, "retains myostatin and GDF11 binding but shows markedly decreased [non-quantifiable] binding to activin A"). This teaching exhibits the complexity and breadth of ActRII ligand traps, as they bind distinct ligands with different affinities.
ActRllA variants that act as ligand traps can comprise a large number of substitutions or combinations of substitutions. However, not all variants retain in vivo activity. For example, US20190345225A1 (filed 2017-11-09, published 2019-11-14; IDS filed 06/05/2025, Cite No. DM; hereinafter referred to as US ‘225) states “[f]or example, an ActRIIA variant having the sequence [SEQ ID NO: 150]... has reduced activity in vivo, indicating that the substitution of alanine (A) for lysine (K) at X17 is not tolerated. ActRIIA variants of the invention... therefore, retain amino acid K at position X17” (¶ 0116).
Claim 43 specifies "X17 is K, A, Y, F, or I" (line 9). As instant SEQ ID NOs: 6-72 include retain amino acid K at position X17, it is not shown that ActRIIA variants wherein X17 is A, Y, F, or I retain in vivo activity in the instant specification.
Applicant is claiming a large and structurally diverse genus of ActRIIA variants comprising numerous substitutions (claim 43). Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which ActRIIA variants (e.g. which substitutions or combinations of substitutions) retain their in vivo activity (e.g. ability to bind ActRIIA ligands).
Treatment of myelofibrosis and cytopenia in a subject having myelofibrosis
The instant specification teaches “ActRIIA/B-mFc can overcome ruxolitinib-induced anemia” in mice (Example 8, ¶ 0255, ruxolitinib is a Jak inhibitor associated with anemia) wherein ActRIIA/B-mFc comprises “SEQ ID NO: 69 fused to a mouse Fc domain by way of a linker” (¶ 0121, Fig. 1). This teaching indicates a combination therapy of ActRIIA/B-mFc and ruxolitinib “has the potential to mitigate the dose limiting effects of ruxolitinib and enhance duration of therapy in myelofibrosis patients” (instant specification, ¶ 0257)
Similarly, US ‘085 teaches ActRIIB-Fc and ruxolitinib treatment in mice is “useful in alleviating Janus kinase inhibitor induced-anemia in a variety of patient populations including, for example, myelofibrosis patients” (Example 10, ¶ 0331).
However, ActRIIA/B-mFc from the instant specification and ActRIIB-Fc from US ‘085 are not antibodies or antigen-binding fragments thereof; they are peptide-Fc fusion proteins.
The instant specification contemplates treatment of ruxolitinib and “ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72}” (Example 10, ¶ 0259) but does not have in vivo or in vitro experiments with all variants. The instant specification does not provides examples using an activin A, myostatin, ActRIl, activin B, and GDF-11 antibodies or antigen binding fragments thereof and a cytopenia-associated myelofibrosis treatment to treat myelofibrosis and cytopenia.
As such, claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are drawn to a method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor, the full scope of which is not enabled by the method as instantly claimed.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors for treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) is well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor for treating a subject having myelofibrosis or cytopenia in a subject having myelofibrosis within the scope of the instant claims is not predictable.
The instant specification teaches “ActRIIA/B-mFc can overcome ruxolitinib-induced anemia” in mice (Example 8, ¶ 0255, ruxolitinib is a Jak inhibitor associated with anemia) wherein ActRIIA/B-mFc comprises “SEQ ID NO: 69 fused to a mouse Fc domain by way of a linker” (¶ 0121, Fig. 1). This teaching indicates a combination therapy of ActRIIA/B-mFc and ruxolitinib “has the potential to mitigate the dose limiting effects of ruxolitinib and enhance duration of therapy in myelofibrosis patients” (instant specification, ¶ 0257)
Similarly, US ‘085 teaches ActRIIB-Fc and ruxolitinib treatment in mice is “useful in alleviating Janus kinase inhibitor induced-anemia in a variety of patient populations including, for example, myelofibrosis patients” (Example 10, ¶ 0331). However, ActRIIA/B-mFc from the instant specification and ActRIIB-Fc from US ‘085 are not antibodies or antigen-binding fragments thereof; they are peptide-Fc fusion proteins.
The instant specification contemplates treatment of ruxolitinib and “ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72}” (Example 10, ¶ 0259) but does not have in vivo or in vitro experiments with all variants. The instant specification does not provides examples using an activin A, myostatin, ActRIl, activin B, and GDF-11 antibodies or antigen binding fragments thereof and a cytopenia-associated myelofibrosis treatment to treat myelofibrosis and cytopenia.
The instant application fails to demonstrate the use of all cytopenia-associated myelofibrosis treatment and all ActRII signaling inhibitors for treating a subject having myelofibrosis or cytopenia in a subject having myelofibrosis within the scope of the instant claims. Cytopenia-associated myelofibrosis treatments include distinct classes of molecules (e.g. HC and Jak inhibitors) with different adverse effects in patients (e.g. general cytopenia or, more specifically, thrombocytopenia, anemia, and neutropenia) (see US ‘085 in the state of the prior art section for more information).
ActRII signaling inhibitors include multiple types of antibodies and antigen binding fragments thereof, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions (see Sifniotis et al. and Sevy and Meiler in state of the prior art section for more information). These antibodies or antigen binding fragments thereof can target ActRII or its ligands. In addition, the instant specification does not specified how to create antigen binding fragments that exhibit the desired biological activity (i.e. retain the ability to bind said antigen) nor the minimal number of CDRs required (i.e. the antigen binding fragment can contain less than 6 CDRs).
ActRII can also be targeted via ligand traps to inhibit ActRII signaling. Ligands of ActRII include "BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF-β1, TGF-β2, TGF-β3, activin A, activin B, activin C, activin E, activin AB, activin AC, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin, MIS, and Lefty" (US ‘085, ¶ 0108). ActRII ligand traps bind distinct ligands with different affinities (US '085, Example 5, ¶ 0312).
The predictability of applying any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor to treat myelofibrosis or cytopenia in a subject having myelofibrosis would be low given that 1) antibodies that inhibit ActRII signaling vary drastically in mechanism of action and it is not clear how to create antigen binding fragments of said antibodies while retaining binding to the desired antigens (see Sifniotis et al. and Sevy and Meiler in state of the prior art section for more information), 2) ActRIIA variants can contained substitutions that lower in vivo activity significantly (see US ‘225 in the state of the prior art section for more information), 3) cytopenia-associated myelofibrosis treatments include distinct classes of molecules (e.g. HC and Jak inhibitors) with different adverse effects in patients (see US ‘085 in the state of the prior art section for more information), and 4) the instant application fails to demonstrate treatment myelofibrosis or cytopenia in a subject having myelofibrosis with all cytopenia-associated myelofibrosis treatments and all ActRII signaling inhibitors (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant specification teaches “ActRIIA/B-mFc can overcome ruxolitinib-induced anemia” in mice (Example 8, ¶ 0255, ruxolitinib is a Jak inhibitor associated with anemia) wherein ActRIIA/B-mFc comprises “SEQ ID NO: 69 fused to a mouse Fc domain by way of a linker” (¶ 0121, Fig. 1). This teaching indicates a combination therapy of ActRIIA/B-mFc and ruxolitinib “has the potential to mitigate the dose limiting effects of ruxolitinib and enhance duration of therapy in myelofibrosis patients” (instant specification, ¶ 0257)
Similarly, US ‘085 teaches ActRIIB-Fc and ruxolitinib treatment in mice is “useful in alleviating Janus kinase inhibitor induced-anemia in a variety of patient populations including, for example, myelofibrosis patients” (Example 10, ¶ 0331). However, ActRIIA/B-mFc from the instant specification and ActRIIB-Fc from US ‘085 are not antibodies or antigen-binding fragments thereof; they are peptide-Fc fusion proteins.
The instant specification contemplates treatment of ruxolitinib and “ActRIIA variant having the sequence of any one of SEQ ID NOs: 1-72 (e.g., SEQ ID NOs: 6-72}” (Example 10, ¶ 0259) but does not have in vivo or in vitro experiments with all variants. The instant specification does not provides examples using an activin A, myostatin, ActRIl, activin B, and GDF-11 antibodies or antigen binding fragments thereof and a cytopenia-associated myelofibrosis treatment to treat myelofibrosis and cytopenia.
The specification does not provide any additional examples or guidance on how to use ActRII signaling inhibitors other than ActRIIA/B-mFc and cytopenia-associated myelofibrosis treatments other than ruxolitinib to treat myelofibrosis or cytopenia in a subject having myelofibrosis as recited in the instant claims (the amount of direction or guidance presented and the presence or absence of working examples). The instant application is not enabled for a method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor.
The amount of experimentation would not be reasonable because it would require determining which cytopenia-associated myelofibrosis treatments and any ActRII signaling inhibitors to use to treat myelofibrosis or cytopenia in a subject having myelofibrosis. Cytopenia-associated myelofibrosis treatments include distinct classes of molecules (e.g. HC and Jak inhibitors) with different adverse effects in patients (e.g. general cytopenia or, more specifically, thrombocytopenia, anemia, and neutropenia) (see US ‘085 in the state of the prior art section for more information).
ActRII signaling inhibitors include multiple types of antibodies and antigen binding fragments thereof, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions (see Sifniotis et al. and Sevy and Meiler in state of the prior art section for more information). These antibodies or antigen binding fragments thereof can target ActRII or its ligands.
ActRII can also be targeted via ligand traps to inhibit ActRII signaling. Ligands of ActRII include "BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF-β1, TGF-β2, TGF-β3, activin A, activin B, activin C, activin E, activin AB, activin AC, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin, MIS, and Lefty" (US ‘085, ¶ 0108). ActRII ligand traps bind distinct ligands with different affinities (US '085, Example 5, ¶ 0312).
Furthermore, the a genus of antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35) and the genus of ActRIIA variants comprising numerous substitutions (claim 43) comprise a diverse class of molecules that require a person having ordinary skill in the art to determine (i) which antigen binding fragments of the activin A, myostatin, activin B, and GDF-11 antibodies retain the ability to bind said antigen and the minimal number of CDRs required (e.g. the antigen binding fragment can contain less than 6 CDRs) and (ii) which ActRIIA variants (e.g. which substitutions or combinations of substitutions) retain their in vivo activity.
It is not routine to determine how such a broad class of molecules would treat myelofibrosis or cytopenia in a subject having myelofibrosis. Undue experimentation would be required to determine whether all cytopenia-associated myelofibrosis treatments and all ActRII signaling inhibitors would treat myelofibrosis or cytopenia in a subject having myelofibrosis (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of the instant claims are extremely broad; it recites multiple cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors to treat myelofibrosis or cytopenia in a subject having myelofibrosis that require the specification of the instant application to provide support for the entire scope of the claim. The specification fails to show that a person having ordinary skill in the art could treat myelofibrosis or cytopenia in a subject having myelofibrosis as recited in the instant claims without undue experimentation.
Cytopenia-associated myelofibrosis treatments include distinct classes of molecules (e.g. HC and Jak inhibitors) with different adverse effects in patients (e.g. general cytopenia or, more specifically, thrombocytopenia, anemia, and neutropenia) (see US ‘085 in the state of the prior art section for more information).
ActRII signaling inhibitors include multiple types of antibodies and antigen binding fragments thereof, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions (see Sifniotis et al. and Sevy and Meiler in state of the prior art section for more information). These antibodies or antigen binding fragments thereof can target ActRII or its ligands.
ActRII can also be targeted via ligand traps to inhibit ActRII signaling. Ligands of ActRII include "BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF-β1, TGF-β2, TGF-β3, activin A, activin B, activin C, activin E, activin AB, activin AC, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin, MIS, and Lefty" (US ‘085, ¶ 0108). ActRII ligand traps bind distinct ligands with different affinities (US '085, Example 5, ¶ 0312).
Furthermore, the a genus of antigen binding fragments that bind activin A, myostatin, activin B, and GDF-11 comprising less than 6 CDRs (claim 35) and the genus of ActRIIA variants comprising numerous substitutions (claim 43) comprise a diverse class of molecules that require a person having ordinary skill in the art to determine (i) which antigen binding fragments of the activin A, myostatin, activin B, and GDF-11 antibodies retain the ability to bind said antigen and the minimal number of CDRs required (e.g. the antigen binding fragment can contain less than 6 CDRs) and (ii) which ActRIIA variants (e.g. which substitutions or combinations of substitutions) retain their in vivo activity.
The field of invention resides in the fields of chemistry and biology, specifically clinical medicine, highly complex and unpredictable arts wherein the treatment of myelofibrosis or cytopenia in a subject having myelofibrosis cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Although claims 1 and 5 broadly recite a method of treating a subject having myelofibrosis (claim 1) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRII signaling inhibitor, the dependent claims demonstrate that practicing the claimed invention encompasses numerous variables.
Collectively, the dependent claims demonstrate that the invention is directed to methods of treating a subject having myelofibrosis (claim 1) or cytopenia in a subject having myelofibrosis (claim 5), subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on the manifestation of the disease in the subject, the specific cytopenia-associated myelofibrosis treatments and ActRII signaling inhibitors administered, and when said medications are administered.
Evidence of efficacy of ActRIIA/B-mFc and ruxolitinib to treat myelofibrosis or cytopenia in a subject having myelofibrosis is provided in the instant specification.
Therefore, the method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of ActRIIA/B-mFc and ruxolitinib is supported. The method of treating a subject having myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor is not supported.
Claim 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to myelofibrosis (claims 1-4, 18, 23-24, 27, 32, 35, 41-43, 45, and 48) or cytopenia in a subject having myelofibrosis (claim 5) comprising administering in combination to the subject an effective amount of any cytopenia-associated myelofibrosis treatment and any ActRII signaling inhibitor with a predictability of success for the reasons outlined above.
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.
Claims 23 and 35 are 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.
Regarding claim 23, the phrase “medium- or high-risk myelofibrosis” renders the claim indefinite because the threshold for medium- and high-risk myelofibrosis is unclear. Medium- or high-risk myelofibrosis is are subjective terms. MPEP 2173.06(b) states: “Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970).” The instant specification does not provide an objective standard for medium- and high-risk myelofibrosis and thus is indefinite.
For the purposes of claim interpretation, the phrase “medium- or high-risk myelofibrosis” will be treated as myelofibrosis with any degree of severity.
Regarding claim 35, the phrase "antibody or antigen binding fragment thereof" renders the claims indefinite because it is unclear whether the claim refers to a full-length antibody or a fragment of an antibody.
For the purposes of claim interpretation, the phrase "antibody or antigen binding fragment thereof" will be interpretated as optionally both a full-length antibody and an antigen binding fragment thereof.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 18, 23-24, 27, 32, 35, 41, 45, and 48 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20180050085 A1 (filed 2017-07-26, published 2018-02-22; hereinafter referred to as US ‘085).
Regarding instant claims 1, 27, and 32, US ‘085 teaches “[Janus kinase] JAK inhibitors have been used to treat myelofibrosis… Moreover, JAK inhibitors have been shown to induce, or worsen, thrombocytopenia” (¶ 0003). This teaching indicates JAK inhibitors (instant claim 27) are cytopenia-associated myelofibrosis treatments (instant claim 1), specifically wherein the cytopenia is thrombocytopenia (instant claim 32).
Regarding instant claim 1, US ‘085 further teaches “methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, comprising administering to a patient in need thereof: a) a Janus kinase inhibitor; and b) an ActRIIB antagonists, wherein the Janus kinase inhibitor and ActRIIB antagonist are administered in an effective amount” (¶ 0008) and the ActRIIB antagonist “inhibits ActRIIB signaling” (¶ 0028). This teaching reads on a method of treating a subject (i.e. a patient) having myelofibrosis, the method comprising the step of administering to the subject an effective amount of a cytopenia-associated myelofibrosis treatment (i.e. a JAK inhibitor) and an ActRIl signaling inhibitor (i.e. an ActRIIB antagonist) (instant claim 1). US ‘085 further teaches “the ActRIIB antagonist is administered concurrently with the Janus kinase inhibitor” (¶ 0010). This teaching reads on the cytopenia-associated myelofibrosis treatment and the ActRIl signaling inhibitor are administered in combination (instant claim 1).
Regarding instant claims 2-5, US ‘085 further teaches the method, specifically referring to the effects of the ActRIIB antagonist, “may be used to treat, prevent, or reduce the progression rate and/or severity of thrombocytopenia in a patient with myelofibrosis” (¶ 0007). This teaching reads on the cytopenia-associated myelofibrosis treatment and the ActRIl signaling inhibitor are administered in combination after the subject has been identified as having a cytopenia (i.e. the method treats patients with existing thrombocytopenia and myelofibrosis; instant claims 2 and 4) or before the subject develops a cytopenia (i.e. the method prevents thrombocytopenia in a patient with myelofibrosis; instant claim 3). This teaching also reads on a method of treating a cytopenia in a subject diagnosed as having myelofibrosis (instant claim 5).
Regarding instant claim 18, US ‘085 further teaches “a patient may be treated with a dosing regimen intended to restore the patient to… allow the reduction or elimination of red blood cell transfusions (reduce transfusion burden)” (¶ 0235). This teaching reads on the method decreasing transfusion burden in a subject (instant claim 18).
Regarding instant claims 23-24, US ‘085 further teaches “the patient has post-essential thrombocythemia myelofibrosis… [or] the patient has high-risk myelofibrosis risk myelofibrosis” (¶ 0006). This teaching reads on the subject has high-risk myelofibrosis (instant claim 23) or post-essential thrombocythemia myelofibrosis (instant claim 24).
Regarding instant claim 35, US ‘085 further teaches “ActRIIB antagonist is an antibody… that binds to ActRIIB” (¶ 0028). This teaching reads on the ActRII signaling inhibitor is an ActRII antibody (instant claim 35).
Regarding instant claims 41 and 45, US ‘085 further teaches “ActRIIB antagonists that inhibit activin can be used in accordance with the methods and uses described herein including, for example, ligand traps” (¶ 0016). This teaching reads on the ActRII signaling inhibitor is an ActRII ligand trap (instant claim 41), specifically an ActRIIB ligand trap (instant claim 45).
Regarding instant claim 48, US ‘085 further teaches “an antibody that binds to ActRIIB inhibits one or more TGF-beta superfamily ligands… [and] antibody is a chimeric antibody” (¶ 0028). This teaching reads on the antibody acts as ActRIIB ligand trap by binding to ActRIIB ligands and thereby reducing ActRIIB signaling and said antibody is chimeric (instant claim 48).
Accordingly, instant claims 1-5, 18, 23-24, 27, 32, 35, 41, 45, and 48 are anticipated by US ‘085.
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 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.
Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over US20180050085A1 (filed 2017-07-26, published 2018-02-22; hereinafter referred to as US ‘085) in view of US20190345225A1 (filed 2017-11-09, published 2019-11-14; IDS filed 06/05/2025, Cite No. DM; hereinafter referred to as US ‘225).
US ‘085 teaches the claims 1-5, 18, 23-24, 27, 32, 35, 41, and 45 as described in the 102 rejection, specifically a method of treating a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap.
US ‘085 does not teach ActRIIA ligand traps nor their sequences.
Regarding instant claim 42, US ‘225 teaches ActRIIA variants that “exhibit improved binding to activins and/or myostatin compared to wild-type ActRIIA, which allows them to compete with endogenous activin receptors for ligand binding and reduce or inhibit endogenous activin receptor signaling” (¶ 0113). This teaching reads on the ActRIIA variants act as ActRIIA ligand traps by binding to ActRIIA ligands and thereby reducing ActRIIA signaling i.e. the ActRIIA variants are ActRIIA signaling inhibitors, specifically ActRIIA ligand traps (instant claim 42).
Regarding instant claim 43, US ‘225 further teaches “[a] polypeptide comprising an extracellular activin receptor type IIa (ActRIIA) variant, the variant having a sequence of (SEQ ID NO: 1)… wherein the variant has at least one amino acid substitution relative to a wild-type extracellular ActRIIA having the sequence of SEQ ID NO: 73” (claim 1 of US ‘225). SEQ ID NOs: 1 and 73 of the instant application are identical to SEQ ID NOs: 1 and 73 of US ‘225 respectively. Note SEQ ID NO: 1 of the instant application and US ‘225 delineate variable amino acid residues for the sequence. This teaching reads on a polypeptide comprising an ActRIIA variant having the sequence of instant SEQ ID NO: 1 and wherein the variant has at least one amino acid substitution relative to wild-type extracellular ActRIIA having the sequence of instant SEQ ID NO: 73 (instant claim 43).
US ‘225 further teaches “[s]tudies have shown that BMP9 binds ActRIIb with about 300-fold higher binding affinity than ActRIIA... ActRIIA is known to have a longer half-life compared to ActRIIb. The present invention describes extracellular ActRIIA variants that are constructed by introducing amino acid residues of ActRIIb to ActRIIA, with the goal of imparting physiological properties conferred by ActRIIb, while also maintaining beneficial physiological and pharmacokinetic properties of ActRIIA” (¶ 0113). This teaching provides motivation for using an ActRIIA variant as it has the enhanced binding capability of ActRIIb while maintaining the longer half-life of ActRIIA.
ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and US ‘225 are in analogous arts (i.e. ActRII ligand traps). Since US ‘225 teaches their ActRIIA variants, applicable to those comprising instant SEQ ID NO: 1, has the enhanced binding capability of ActRIIb while maintaining the longer half-life of ActRIIA, there is motivation for using the ActRIIA variant comprising instant SEQ ID NO: 1 as taught in US ‘225 in a method of treating a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. the ActRIIA variant, applicable to those comprising instant SEQ ID NO: 1, has the enhanced binding capability of ActRIIb while maintaining the longer half-life of ActRIIA as taught in US ‘225) would have led one of ordinary skill to modify the prior art reference (i.e. a method of treating a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085) to arrive at the claimed invention. There is a reasonable expectation of success as ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and US ‘225 are in analogous arts (i.e. ActRII ligand traps).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the ActRIIA variant comprising instant SEQ ID NO: 1 as taught by US ‘225 for the specific ActRII ligand trap in a method of treating a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
Accordingly, instant claims 42-43 are rendered obvious over US ‘085 in view of US ‘225.
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.
Claim 1, 5, 32, and 41-43 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2 and 6-8 of U.S. Patent No. 12364737 (hereinafter referred to as Pat. ‘737) in view of US20180050085A1 (filed 2017-07-26, published 2018-02-22; hereinafter referred to as US ‘085) as evidenced by US20190345225A1 (filed 2017-11-09, published 2019-11-14; IDS filed 06/05/2025, Cite No. DM; hereinafter referred to as US ‘225).
Instant claims 1 and 5 teach a method of treating a subject having myelofibrosis (instant claim 1) or cytopenia in a subject having myelofibrosis (instant claim 5), the method comprising the step of administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRII signaling inhibitor. Instant claim 32 teaches the cytopenia is anemia. Instant claim 41-42 teach the ActRII signaling inhibitor is an ActRII ligand trap (instant claim 41), specifically an ActRIIA ligand trap (instant claim 42). Instant claim 43 teaches the ActRIIA ligand trap comprises a polypeptide comprising an extracellular ActRIIA variant having a sequence of SEQ ID NO: 1 with multiple variable amino acid residues, and the variant has at least one amino acid substitution relative to a wild-type extracellular ActRlla having the sequence of SEQ ID NO: 73.
Claim 1 of Pat. ‘737 teaches a method of treating anemia in a subject diagnosed as having anemia associated with myelofibrosis, comprising: (i) measuring the subject's hemoglobin levels, followed by (ii) administering to the subject a therapeutically effective amount of a polypeptide comprising an extracellular ActRIIA variant, the variant having a sequence of SEQ ID NO: 1 with multiple variable amino acid residues. The instant specification includes anemia in its definition of cytopenia (¶ 0088, cytopenia “e.g., anemia, thrombocytopenia, or neutropenia”), reading on instant claim 5.
US ‘225 teaches ActRIIA variants comprising SEQ ID NO: 1 of Pat. ‘737 “exhibit improved binding to activins and/or myostatin compared to wild-type ActRIIA, which allows them to compete with endogenous activin receptors for ligand binding and reduce or inhibit endogenous activin receptor signaling” (¶ 0113). This teaching reads on the ActRIIA variants act as ActRIIA ligand traps by binding to ActRIIA ligands and thereby reducing ActRIIA signaling. The ActRIIA variants of Pat. ‘737 are ActRIIA ligand traps that inhibit ActRIIA signaling as evidenced by US ‘225 (instant claim 41-42).
Claim 6 of Pat. ‘737 teaches X1 is F and X10 is K in SEQ ID NO: 1. SEQ ID NO: 1 of both Pat. ‘737 and the instant application have the same consensus sequence and variable amino acid residue positions. Although the instant application permits additional, alternative amino acids at certain variable amino acid residues, the identities of all variable amino acid residues as taught in claims 1 and 6 of Pat ‘737 are taught in instant SEQ ID NO: 1. Thus, instant SEQ ID NO: 1 overlaps and encompasses SEQ ID NO: 1 of Pat. ‘737 (instant claim 43).
Claims 2 and 7-8 of Pat. ‘737 teaches the variant has the sequence of one of SEQ ID NOs: 6-72. Instant SEQ ID NO: 1 overlaps and encompasses SEQ ID NOs: 6-72 of Pat. ‘737 (instant claim 43).
Claims 1-2, 6-8 of Pat. ‘785 do not teach a method of treating myelofibrosis nor administration of a cytopenia-associated myelofibrosis treatment in combination with the ActRIIA ligand trap.
US ‘085 teaches the claims 1, 5, 32, and 41 as described in the 102 rejection, specifically a method of treating a subject having myelofibrosis and cytopenia in a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap.
US ‘085 does not teach ActRIIA ligand traps nor their sequences.
ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and Pat. ‘737 are in analogous arts (i.e. methods of treating cytopenia in a subject having myelofibrosis with ActRII ligand traps). Since US ‘085 teaches ActRII ligand traps can be used in combination with JAK inhibitors to effectively treat myelofibrosis and cytopenia in a subject having myelofibrosis, there is motivation for using the ActRIIA variants as taught in Pat. ‘737 in a method of treating a subject having myelofibrosis and cytopenia in a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. ActRII ligand traps can be used in combination with JAK inhibitors to effectively treat myelofibrosis and cytopenia in a subject having myelofibrosis as taught in US ‘085) would have led one of ordinary skill to modify Pat. ‘737 (i.e. ActRIIA variants, acting as ligand traps, and their sequences) to arrive at the claimed invention. There is a reasonable expectation of success as ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and Pat. ‘737 are in analogous arts (i.e. methods of treating cytopenia in a subject having myelofibrosis with ActRII ligand traps).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the ActRIIA variants as taught by Pat. ‘737 for the specific ActRII ligand trap in a method of treating a subject having myelofibrosis and cytopenia in a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
Claim 41-43 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 7, and 9 of U.S. Patent No. 11013785 (hereinafter referred to as Pat. ‘785) in view of US20180050085A1 (filed 2017-07-26, published 2018-02-22; hereinafter referred to as US ‘085) as evidenced by US20190345225A1 (filed 2017-11-09, published 2019-11-14; IDS filed 06/05/2025, Cite No. DM; hereinafter referred to as US ‘225).
Instant claims 41-42 teaches a method of treating a subject having myelofibrosis, the method comprising the step of administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRII ligand trap (instant claim 41), specifically an ActRIIA ligand trap (instant claim 42). Instant claim 43 teaches the ActRIIA ligand trap comprises a polypeptide comprising an extracellular ActRIIA variant having a sequence of SEQ ID NO: 1 with multiple variable amino acid residues, and the variant has at least one amino acid substitution relative to a wild-type extracellular ActRlla having the sequence of SEQ ID NO: 73.
Claim 1 of Pat. ‘785 teaches a polypeptide comprising an extracellular ActRIIA variant and an Fc domain, the variant having a sequence of SEQ ID NO: 1 with multiple variable amino acid residues. Claim 8 of Pat ‘785 teaches X1 is F and X10 is K in SEQ ID NO: 1. SEQ ID NO: 1 of both Pat. ‘785 and the instant application have the same consensus sequence and variable amino acid residue positions. Although the instant application permits additional, alternative amino acids at certain variable amino acid residues, the identities of all variable amino acid residues as taught in claims 1 and 8 of Pat ‘785 are taught in instant SEQ ID NO: 1. Thus, instant SEQ ID NO: 1 overlaps and encompasses SEQ ID NO: 1 of Pat. ‘785 (instant claim 43).
Claims 2, 7, and 9 of Pat. ‘785 teaches the variant has the sequence of one of SEQ ID NOs: 6-72. Instant SEQ ID NO: 1 overlaps and encompasses SEQ ID NOs: 6-72 of Pat. ‘785 (instant claim 43).
US ‘225 teaches ActRIIA variants comprising SEQ ID NO: 1 of Pat. ‘785 “exhibit improved binding to activins and/or myostatin compared to wild-type ActRIIA, which allows them to compete with endogenous activin receptors for ligand binding and reduce or inhibit endogenous activin receptor signaling” (¶ 0113). This teaching reads on the ActRIIA variants act as ActRIIA ligand traps by binding to ActRIIA ligands and thereby reducing ActRIIA signaling. The ActRIIA variants of Pat. ‘785 are ActRIIA ligand traps that inhibit ActRIIA signaling as evidenced by US ‘225 (instant claim 41-42).
Claims 1-2, 7, and 9 of Pat. ‘785 do not teach a method of treating a subject having myelofibrosis, the method comprising the step of administering in combination to the subject an effective amount of a cytopenia-associated myelofibrosis treatment and an ActRIIA ligand trap.
ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and Pat. ‘785 are in analogous arts (i.e. ActRII ligand traps). Since US ‘085 teaches ActRII ligand traps can be used in combination with JAK inhibitors to effectively treat myelofibrosis and cytopenia in a subject having myelofibrosis, there is motivation for using the ActRIIA variants as taught in Pat. ‘785 in a method of treating a subject having myelofibrosis and cytopenia in a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. ActRII ligand traps can be used in combination with JAK inhibitors to effectively treat myelofibrosis and cytopenia in a subject having myelofibrosis as taught in US ‘085) would have led one of ordinary skill to modify Pat. ‘785 (i.e. ActRIIA variants, acting as ligand traps, and their sequences) to arrive at the claimed invention. There is a reasonable expectation of success as ActRIIA ligand traps and their sequences were known and used prior to the effective filing date of the application. In addition, both US ‘085 and Pat. ‘785 are in analogous arts (i.e. ActRII ligand traps).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the ActRIIA variants as taught by Pat. ‘785 for the specific ActRII ligand trap in a method of treating a subject having myelofibrosis and cytopenia in a subject having myelofibrosis comprising administering in combination to the subject an effective amount of a JAK inhibitor and an ActRII ligand trap as taught in US ‘085.
Conclusion
Claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are pending. Claims 1-5, 18, 23-24, 27, 32, 35, 41-43, 45, and 48 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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