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 the following species in the reply filed on 2/25/26 is acknowledged:
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Claim Status
Claims 1, 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 are pending and under examination.
Claims 2-31, 36, 39, 40, 42, 47, 48, 52, 54, 59, 64, 67, 68 are cancelled.
Claims 1, 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 are rejected.
Priority
The instant application, filed 05/04/2023 is a National Stage entry of PCT/US2021/058068 , International Filing Date: 11/04/2021
PCT/US2021/058068 Claims Priority from Provisional Application 63110844 , filed 11/06/2020
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 10/4/23, 12/12/24, 9/4/25 and 2/25/26 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Claim Objections
Claim 1 is objected to because of the following informalities: in line 4 “monitoring a subject’s response” should be amended to “monitoring a response in the subject” to indicate this is a response in the line 2 subject. Appropriate correction is required.
Claim Interpretation
Claim 71’s “an amino acid sequence of SEQ ID NO:3” is interpreted to encompass polypeptide sequences that are shorter than but a portion of SEQ ID NO:3, and also given the open term “comprises” the polypeptide encompasses longer polypeptides that include the entire SEQ ID NO:3 as well as polypeptide sequences that are shorter than but a portion of SEQ ID NO:3.
Claim Rejections - 35 USC § 112
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 1, 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed subject matter is not supported by an adequate written description. An “human ActRII polypeptide linked to a constant domain of an immunoglobulin” is required to practice the claimed method. There is insufficient descriptive support for the genus "human ActRII polypeptides”. The specification gives a broad teaching that includes per para 72, “In certain embodiments, the lyophilized polypeptide comprises an ActRII polypeptide (e.g., a polypeptide that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2 or SEQ ID NO: 3), or fragments, functional variants, or modified forms thereof. In certain embodiments, the polypeptide binds to one or more ligands selected from the group consisting of activin A, activin B, and GDF11. In certain such embodiments, the polypeptide further binds to one or more ligands selected from the group consisting of BMP10, GDF8, and BMP6. In certain embodiments, the polypeptide binds to activin and/or GDF11,” and in para 73 broadly states, “In some embodiments, the lyophilized polypeptide comprises a polypeptide that comprises, consists essentially of, or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2 or SEQ ID NO: 3.”
There is no relevant teaching, structure/function disclosure, and/or examples that instruct what are the key or critical components, arrangements, amino acids in specific locations, that result in a polypeptide provides the activity that is needed for effective treatment as instantly claimed. There is no information regarding what structural features would likely be associated with such activity. The disclosure does not allow one of skill in the art to visualize or recognize the structure of a sufficient number and diversity of species of the “human ActRII polypeptide linked to a constant domain of an immunoglobulin” required to practice the claimed method.
The skilled artisan cannot envision the detailed chemical structure of the entire genus of “human ActRII polypeptide linked to a constant domain of an immunoglobulin” species which have the activity without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. 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 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). 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, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112, first paragraph. Applicants are 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).
Claim 71 additionally is 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.
Although the specification discloses aspects of the ActRII polypeptide that pertain to its activities, paras 94-99, there are insufficient teachings, descriptions of structure/function relationships, data and examples regarding how to construct the polypeptides shorter than SEQ ID NO:3 that function as ActRII polypeptides to be in possession of the entire genus of claim 71 as interpreted, see Claim Interpretation above.
Applicant can overcome this basis of rejection in claim 71 by amendment of claim 71 to make clear that shorter portions of SEQ ID NO:3 are not encompassed by the claim.
Claims 1, 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 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 the claim 1 method when the human ActRII linked to a constant domain of an immunoglobulin is SEQ ID NO:3, does not reasonably provide enablement for any human ActRII linked to a constant domain of an immunoglobulin that is encompassed by the genus of human ActRII polypeptide linked to a constant domain of an immunoglobulin. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The specification is not enabling for the full scope for the following reasons:
1. The specification focuses on a method that includes a monitoring step, but does not define nor go into sufficient detail as to what are the structural limitations of the human ActRII linked to a constant domain of an immunoglobulin.
2. Furthermore, the description of a polypeptide sequence comprising at least 85%, 90% or 95% identity to SEQ ID NO:3 (these also claimed in claims 32, 69 and 70) represents a partial structure. At least 5-15% of the amino acids can vary from those sequences recited in the claims. The specification fails to teach which regions of the ActRII polypeptide is responsible for the interactions underlying its biological functions of thalassemia or myelodysplastic syndrome treatment. It is well recognized in the art, any modification (even a "conservative" substitution) to a critical structural region of a protein is likely to significantly alter its functional properties. It is known for nucleic acids as well as proteins, that even a single nucleotide or amino acid change or mutation can destroy the function of the biomolecule in many cases. See Tokuriki, (Stability effects of mutations and protein evolvability; Current Opinion in Structural Biology, 19:596-604, 2009) and Bhattacharya et al. (Impact of genetic variation on three dimensional structure and function of proteins; PLOS One 12(3): e0171355, pages 1-22, March 2017.
3. It is noted that the broadest claim 1 is drawn to administering any human ActRII polypeptide linked to a constant domain of an immunoglobulin. The claims depend on a recited property/activity, where the claim covers every conceivable structure for achieving the stated property/activity while the specification discloses only those known to the inventor. It is important to note that an assay for finding a product is not equivalent to a positive recitation of how to make a product. In the instant case, the artisan would accordingly have no resort but trial-and-error experimentation to determine which of the large number of possible structural variants had the same functional properties. Such experimentation would be undue for one skilled in this art.
Due to the large quantity of experimentation necessary to make any human ActRII polypeptide linked to a constant domain of an immunoglobulin and screen the same for the activity of being able to treat thalassemia or myelodysplastic syndrome treatment in subjects, without knowing the structural features that are required in order to provide the claimed activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to same; the complex nature of the invention; the state of the art which establishes the unpredictability of the effects of mutations on protein structure and function; and the inherent unpredictability regarding the type of effects administered human ActRII polypeptides linked to a constant domain of an immunoglobulin would have when administered to treat thalassemia or myelodysplastic syndrome patients, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 112
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 1, 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 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.
Claim 1 recites “an initial dose of 1 mg/kg”. It is unclear whether this mg amount refers to the human ActRII polypeptide apart from the constant domain of an immunoglobulin to which it is linked, or to the entire construct that includes the constant domain of an immunoglobulin. The specification refers to ActRII polypeptides at times without reference to being linked to a constant domain of an immunoglobulin, such as paras 29-33 of the corresponding PGPUB, and at other times indicating that this is linked to a constant domain of an immunoglobulin, such as para 24. One of ordinary skill in the art cannot reasonably determine whether the mg of the mg/kg dosage refers only to the ActRII polypeptide without the constant domain of an immunoglobulin, or to the combined fusion protein that includes the constant domain of an immunoglobulin.
Claim 1 recites the limitation "the subsequent dose" twice in line 4, the first instance lacking antecedent basis earlier in the claim. There is insufficient antecedent basis for this limitation in the claim. This can be corrected by amending the first "the subsequent dose" to "a subsequent dose" so long as this is supported in the application as filed.
Claims 32, 34, 35, 37, 38, 41, 43-46, 49-51, 53, 55-58, 60-63, 65, 66, 69-71 depending from claim 1 do not overcome these bases of rejection and also are rejected based on the claim 1 rejection above.
Additionally, claims 60 and 65 are rejected because each of these recite a w/v, weight per volume value, but there is no volume stated or implied in these claims nor in claims from which they depend. It is unclear what the volume is – a volume of lyophilized ActRII polypeptide in a vial or other container before administering or reconstituting, or some volume after reconstitution, which the claims from which these claims depend are silent on, only claim 41, not in these claim dependency chains, adding reconstitution (and not indicating a specific volume given that claim 38 from which it depends includes both 25 mg/vial and 75 mg/vial of the polypeptide that in claim 41 has a final concentration of approximately 50 mg/ml). One of ordinary skill in the art cannot reasonably ascertain the metes and bounds of what is claimed in claims 60 and 65 because there is no clear reference to the volume of the w/v denominator.
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.
Claim(s) 1, 32, 35, 37, 38, 45, 46, 51, 53, 55, 56, 57, 58, 60, 61, 62, 63, 66, 69, 70, and 71 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2016/183280 A1, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS).
The elected species are set forth above.
Claim 1 is directed to “A dosing regimen for the treatment of thalassemia or myelodysplastic syndrome in a subject in need thereof comprising administering a lyophilized human ActRII polypeptide linked to a constant domain of an immunoglobulin, wherein the dosing regimen comprises: 1) administering an initial dose of 1 mg/kg; 2) monitoring a subject's response; and 3) modifying the subsequent dose; and wherein the subject is administered the subsequent dose every three weeks.”
Attie teaches treating thalassemia, Title, paras 3, 9, 12 (including administering an activin receptor type II (ActRII) signaling inhibitor subcutaneously toe the subject every 21 days (~ 3 weeks), and in multiple additional paragraphs.
Attie teaches administering its SEQ ID NO:25, which per below comparison is identical to instantly elected SEQ ID NO:3, subcutaneously once every 21 days (~3 weeks), starting at a 1 mg/kg dose level, page 122, para 408, see also paras 33, 38, 39, 69, 93 and elsewhere, clearly establishing that this peptide is one of the administered ActRII-Fc moieties of its invention.
Comparison with Attie’s SEQ ID NO:25 indicates the same polypeptide as instant SEQ ID NO:3:
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Attie teaches monitoring a subject’s response after the administering, see paras 101, 102, Table 1 thereafter, 103 and Table 2 thereafter, 104-107, 110-114 and 259, these clearly teaching that hemoglobin concentration is monitored in the subject and modifying a subsequent dose is taught based on that monitoring. These paras and tables also indicate a 21 day, that is three week, interval in administering doses.
Attie para 316 teaches in part, “In another preferred embodiment, the ActRII signaling inhibitor is packaged in a container as a sterile, preservative-free lyophilized powder or cake. In certain embodiments, the container comprises 25 mg of the ActRII signaling inhibitor. In certain embodiments, the container comprising 25 mg of the ActRII signaling inhibitor comprises a total of 37.5 mg of protein. In certain embodiments, ActRII signaling inhibitor in the container comprising 25 mg of the ActRII signaling inhibitor is reconstituted with 0.68 mL of water for injection. … In certain embodiments, the container comprising 75 mg of the ActRII signaling inhibitor comprises a total of 87.5 mg of protein. In certain embodiments, ActRII signaling inhibitor in the container comprising 75 mg of the ActRII signaling inhibitor is reconstituted with 1.6 mL of water for injection. In certain embodiments, the ActRII signaling inhibitor in the container is reconstituted with a volume of water for injection, such that the final concentration of the reconstituted ActRII signaling inhibitor in the water for injection is 50 mg/mL with a pH of approximately 6.5.… In certain embodiments, the container is a 3 mL glass vial with a gray butyl coated stopper. In certain embodiments, the container is a 3 mL glass vial with a gray rubber stopper. In certain embodiments, the rubber stopper is secured in place by a crimped aluminum flip cap with a colored plastic button. In certain embodiments, the 3 mL glass vial comprises 25 mg of the ActRII signaling inhibitor and the the colored plastic button is red. In certain embodiments, 3 mL glass vial comprises 75 mg of the ActRII signaling inhibitor and the the colored plastic button is white.” This meets the second elected species.
Attie teaches in para 317 “In a specific embodiment, the ActRII signaling inhibitor is packaged in a container as a sterile, preservative-free lyophilized powder or cake. In a specific embodiment, the container comprises 50 mg/mL of ActRII signaling inhibitor in 10 mM citrate buffer pH 6.5. In a specific embodiment, the container comprises 56 mg of ActRII signaling inhibitor, 0.19 mg of citric acid monohydrate, 3 .03 mg of tri-sodium citrate dehydrate, 0.24 mg of polysorbate 80, and 100.80 mg of sucrose,” meeting the third elected species regarding additional additives/excipients.
Attie anticipates claims 1, 32, 35, 37, 38, 45, 46, 51, 53, 55, 56, 57, 58, 60 (because from para 317 100.80/(56 + 0.19 + 3.03 + 0.24 + 100.80) = 62.9% on a w/w basis without reconstituting, the examiner noting that reconstituting is not required by claim 60 nor by claims from which it depends1, and this 62.9% greatly exceeds 9%), 61, 62, 63, 66, 69, 70, and 71.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 41, 43, 44, 49, 50 are rejected under 35 U.S.C. 103 as being unpatentable over by WO 2016/183280 A1, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied to claims 1, 38, 45, 46, and further in view of REBLOZYL® Dosing and Reconstitution Guide, 16 pages, July 2020 (“Guide”).
The rejection of claim 1 is set forth above.
Attia teaches reconstituting with water, but does not explicitly teach that this water is sterile water (although Attia teaches its container/vial contents are sterile).
The level of ordinary skill in the art is high.
Guide teaches reconstituting its REBLOZYL® for injection with sterile water, pages 10 and 11. Given that this Guide teaches administering the same active ingredient as instantly claimed (or a nearly identical ingredient in the same class), and additionally given the knowledge in the art and general practice among clinicians to maintain sterility of parenterally administered therapeutic compositions, one of ordinary skill in the art would reasonably have understood the importance of using sterile water to reconstitute the contents of the Attie containers/vials, and would have used sterile water. There would have been a reasonable expectation of success given the teachings of Guide. (Please note that pages 4-7 of Guide also teach dose modification based on monitoring RBC and/or Hgb levels.)
Accordingly, claims 41, 43, 44, 49, 50 would have been obvious and are rejected under this section.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over by WO 2016/183280 A1, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied above to claim 1, and further in view of WO/2017/079591, inventors Kumar et al., published 5/11/2017 (“Kumar”, provided in 10/4/23 IDS) and Mcauley et al., Protein Science (2008), 17:95–106 (“Mcauley”).
The rejection of claim 1 is set forth above.
Attia does not teach that its polypeptide “is part of a homodimer protein complex.”
The level of ordinary skill in the art is high.
Kumar, Example 2, characterizing one of its ActRIIA-humanFc Proteins, teaches, “ Protein analysis reveals that the ActRIIA-hFc fusion protein is formed as a homodimer with disulfide bonding.”
Mcauley, studying the dimerization of human IgG1 antibody CH3 domain of heavy chain constant regions, states that “dimerization of the CH3 domain in the constant region of the heavy chain plays a pivotal role in the assembly of an antibody. This domain contains a single buried, highly conserved disulfide bond. This disulfide bond was not required for dimerization, since a recombinant human CH3 domain, even in the reduced state, existed as a dimer,” Abstract. However, further in the Abstract, “Thus, disulfide bond formation in the human CH3 domain is important for stability and dimerization. Here we show the importance of the role played by the disulfide bond and how it affects the stability and monomer–dimer equilibrium of the human CH3 domain. Hence, these results may have implications for the stability of the intact antibody.”
Based on these teachings, merely the presence of the Fc domain in the Attie SEQ ID NO:25 would result in at least some dimer formation, and based on the Redox conditions of any solution thereof, the equilibrium toward or away from dimerization may be influenced.
As such, one or ordinary skill in the art would have recognized that the Attie polypeptide corresponding to SEQ ID NO:25 (identical to instant SEQ ID NO:3 as above) would exist in an equilibrium when in solution such that at least some of such polypeptide “is part of a homodimer protein complex.” There would have been a reasonable expectation of success based on the clear teachings of Kumar and Mcauley as to the formation of dimers and factors for such formation.
Accordingly, claim 34 would have been obvious and is rejected under this section.
Claim 65 is rejected under 35 U.S.C. 103 as being unpatentable over by WO 2016/183280 A1, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied above to claims 1, 37, 45, 61 and further in view of Agarkhed et al., AAPS PharmSciTech, Vol. 14, No. 1, March 2013, 9 pages and Nuijen, Abstract of Drug Development and Industrial Pharmacy, Volume 27, 2001 - Issue 8, pp 767-780 (only Abstract provided).
Claim 65 requires that the surfactant comprises a concentration of at least 0.2% w/v, although there is no volume requirement or limitation in claim 65 nor preceding claims from which claim 65 depends. For purposes of this rejection this is interpreted as w/w basis.
Attie in its embodiment that includes polysorbate 80 at 0.24 grams, see above, results in 0.24/(56 + 0.19 + 3.03 + 0.24 + 100.80) = 0.15% on a w/w basis without reconstituting, the examiner noting that reconstituting is not required by claim 60 nor by claims from which it depends.
This is close to but not at least 0.2%.
Agarkhed teaches an optimization of polysorbate 80 concentration for thermal and photostability of a monoclonal antibody, Title, Abstract, and in the Abstract states, “This study demonstrates the importance of carefully choosing Polysorbate 80 concentration in protein formulations to prevent destabilizing effect of Polysorbate 80 on thermal and photostability.” Agarkhed teaches that the concentration of polysorbate 80 is a result-effective variable and amenable to routine optimization.
Nuijen, Abstract, teaches that for a different subject polypeptide, a study was done to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. This study included evaluating different concentrations of polysorbate 80 and citric acid when used with either mannitol or sucrose as bulking agents when preparing solutions for freeze-drying, and included studies upon reconstitution of lyophilized products. “It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a bulking agent were more stable compared to the products containing mannitol.” This further establishes that concentrations of polysorbate 80 and citric acid are known to be result-effective when considering solubility and stability of polypeptides that are to be lyophilized and then used as a therapeutic agent.
It would have been obvious to further evaluate polysorbate 80 concentrations, including those higher than the 0.24 g used in one embodiment by Attie, and arrive at a concentration that is at least 0.2%, by routine optimization. There would have been a reasonable expectation of success given the teachings of Agarkhed.
Accordingly, claim 65 is rejected as obvious under this section.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 32, 69-71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 8, 11-13, 17, 18, 20 of U.S. Patent No. 11471510 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent claims also teach monitoring and adjusting dosage following an initial administering, the latter including administering its SEQ ID NO:25 which is identical with instant SEQ ID NO:3, see comparison below, and evaluates hematological parameters that include hemoglobin level and RBC.
Comparison instant seq id no: 3 with seq id no: 25 of ‘510:
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Claims 35, 37, 38, 45, 46, 51, 53, 55, 56, 57, 58, 60, 61, 62, 63, 66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 8, 11-13, 17, 18, 20 of U.S. Patent No. 11471510 (reference patent) in view of WO 2016/183280 Al, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS).
The rejection of claim 1 is set forth above. Reference patent claims do not teach many limitations of the noted dependent claims, however the level of ordinary skill in the art is high and Attie teaches in the same field relevant limitations known in the art.
Attie teaches treating thalassemia, Title, paras 3, 9, 12 (including administering an activin receptor type II (ActRII) signaling inhibitor subcutaneously toe the subject every 21 days (~ 3 weeks), and in multiple additional paragraphs.
Attie teaches administering its SEQ ID NO:25, which per below comparison is identical to instantly elected SEQ ID NO:3, subcutaneously once every 21 days (~3 weeks), starting at a 1 mg/kg dose level, page 122, para 408, see also paras 33, 38, 39, 69, 93 and elsewhere, clearly establishing that this peptide is one of the administered ActRII-Fc moieties of the invention.
Comparison with Attie’s SEQ ID NO:25 indicates the same polypeptide as instant SEQ ID NO:3:
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Greyscale
Attie teaches monitoring a subject’s response after the administering, see paras 101, 102, Table 1 thereafter, 103 and Table 2 thereafter, 104-107, 110-114 and 259, these clearly teaching that hemoglobin concentration is monitored in the subject and modifying a subsequent dose is taught based on that monitoring. These paras and tables also indicate a 21 day, that is three week, interval in administering doses.
Attie para 316 teaches in part, “In another preferred embodiment, the ActRII signaling inhibitor is packaged in a container as a sterile, preservative-free lyophilized powder or cake. In certain embodiments, the container comprises 25 mg of the ActRII signaling inhibitor. In certain embodiments, the container comprising 25 mg of the ActRII signaling inhibitor comprises a total of 37.5 mg of protein. In certain embodiments, ActRII signaling inhibitor in the container comprising 25 mg of the ActRII signaling inhibitor is reconstituted with 0.68 mL of water for injection. … In certain embodiments, the container comprising 75 mg of the ActRII signaling inhibitor comprises a total of 87.5 mg of protein. In certain embodiments, ActRII signaling inhibitor in the container comprising 75 mg of the ActRII signaling inhibitor is reconstituted with 1.6 mL of water for injection. In certain embodiments, the ActRII signaling inhibitor in the container is reconstituted with a volume of water for injection, such that the final concentration of the reconstituted ActRII signaling inhibitor in the water for injection is 50 mg/mL with a pH of approximately 6.5.… In certain embodiments, the container is a 3 mL glass vial with a gray butyl coated stopper. In certain embodiments, the container is a 3 mL glass vial with a gray rubber stopper. In certain embodiments, the rubber stopper is secured in place by a crimped aluminum flip cap with a colored plastic button. In certain embodiments, the 3 mL glass vial comprises 25 mg of the ActRII signaling inhibitor and the the colored plastic button is red. In certain embodiments, 3 mL glass vial comprises 75 mg of the ActRII signaling inhibitor and the the colored plastic button is white.” This meets the second elected species.
Attie teaches in para 317 “In a specific embodiment, the ActRII signaling inhibitor is packaged in a container as a sterile, preservative-free lyophilized powder or cake. In a specific embodiment, the container comprises 50 mg/mL of ActRII signaling inhibitor in 10 mM citrate buffer pH 6.5. In a specific embodiment, the container comprises 56 mg of ActRII signaling inhibitor, 0.19 mg of citric acid monohydrate, 3 .03 mg of tri-sodium citrate dehydrate, 0.24 mg of polysorbate 80, and 100.80 mg of sucrose,” meeting the third elected species regarding additional additives/excipients.
In view of claims 1-3, 7, 8, 11-13, 17, 18, 20 of the reference patent, when also considering the related teachings of Attie, claims 35, 37, 38, 45, 46, 51, 53, 55, 56, 57, 58, 60 (because from para 317 100.80/(56 + 0.19 + 3.03 + 0.24 + 100.80) = 62.9% on a w/w basis without reconstituting, the examiner noting that reconstituting is not required by claim 60 nor by claims from which it depends, and this 62.9% greatly exceeds 9%), 61, 62, 63, 66, are rejected under this section.
Claims 41, 43, 44, 49, 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 8, 11-13, 17, 18, 20 of U.S. Patent No. 11471510 (reference patent) in view of WO 2016/183280 Al, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied to claims 1, 38, 45, 46, and further in view of REBLOZYL® Dosing and Reconstitution Guide, 16 pages, July 2020 (“Guide”).
The rejection of claims 1, 38, 45, 46 are set forth above.
Neither reference patent claims nor Attia teach reconstituting with sterile water (although Attia teaches its container/vial contents are sterile).
The level of ordinary skill in the art is high.
Guide teaches reconstituting its REBLOZYL® for injection with sterile water, pages 10 and 11. Given that this Guide teaches administering the same active ingredient as instantly claimed (or a nearly identical ingredient in the same class), and additionally given the knowledge in the art and general practice among clinicians to maintain sterility of parenterally administered therapeutic compositions, one of ordinary skill in the art would reasonably have understood the importance of using sterile water to reconstitute the contents of the Attie containers/vials, and would have used sterile water. There would have been a reasonable expectation of success given the teachings of Guide. (Please note that pages 4-7 of Guide also teach dose modification based on monitoring RBC and/or Hgb levels.)
Accordingly, considering the teachings of reference patent claims 1-3, 7, 8, 11-13, 17, 18, 20 in view of the secondary references’ teachings, claims 41, 43, 44, 49, 50 would have been obvious and are rejected under this section.
Claim 34 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 8, 11-13, 17, 18, 20 of U.S. Patent No. 11471510 (reference patent) in view of WO 2016/183280 Al, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied above to claim 1, and further in view of WO/2017/079591, inventors Kumar et al., published 5/11/2017 (“Kumar”, provided in 10/4/23 IDS) and Mcauley et al., Protein Science (2008), 17:95–106 (“Mcauley”).
The rejection of claim 1 is set forth above.
Neither reference patent claims nor Attia teach that its polypeptide “is part of a homodimer protein complex.”
The level of ordinary skill in the art is high.
Kumar, Example 2, characterizing one of its ActRIIA-humanFc Proteins, teaches, “ Protein analysis reveals that the ActRIIA-hFc fusion protein is formed as a homodimer with disulfide bonding.”
Mcauley, studying the dimerization of human IgG1 antibody CH3 domain of heavy chain constant regions, states that “dimerization of the CH3 domain in the constant region of the heavy chain plays a pivotal role in the assembly of an antibody. This domain contains a single buried, highly conserved disulfide bond. This disulfide bond was not required for dimerization, since a recombinant human CH3 domain, even in the reduced state, existed as a dimer,” Abstract. However, further in the Abstract, “Thus, disulfide bond formation in the human CH3 domain is important for stability and dimerization. Here we show the importance of the role played by the disulfide bond and how it affects the stability and monomer–dimer equilibrium of the human CH3 domain. Hence, these results may have implications for the stability of the intact antibody.”
Based on these teachings, merely the presence of the Fc domain in the Attie SEQ ID NO:25 would result in at least some dimer formation, and based on the Redox conditions of any solution thereof, the equilibrium toward or away from dimerization may be influenced.
As such, one or ordinary skill in the art would have recognized that the Attie polypeptide corresponding to SEQ ID NO:25 (identical to instant SEQ ID NO:3 as above) would exist in an equilibrium when in solution such that at least some of such polypeptide “is part of a homodimer protein complex.” There would have been a reasonable expectation of success based on the clear teachings of Kumar and Mcauley as to the formation of dimers and factors for such formation.
Accordingly, considering the reference patent claims and the teaching of the secondary references, claim 34 would have been obvious and is rejected under this section.
Claim 65 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 8, 11-13, 17, 18, 20 of U.S. Patent No. 11471510 (reference patent) in view of WO 2016/183280 Al, inventors Attie et al., published 11/17/2016 (“Attie”, provided in 12/12/24 IDS), as applied above to claims 1, 37, 45, 61, and further in view of Agarkhed et al., AAPS PharmSciTech, Vol. 14, No. 1, March 2013, 9 pages, and Nuijen, Abstract of Drug Development and Industrial Pharmacy, Volume 27, 2001 - Issue 8, pp 767-780 (only Abstract provided).
Claims 1, 37, 45, 61 are rejected above.
Claim 65 requires that the surfactant comprises a concentration of at least 0.2% w/v, although there is no volume requirement or limitation in claim 65 nor preceding claims from which claim 65 depends. For purposes of this rejection this is interpreted as w/w basis.
Reference patent claims do not teach this limitation, and the level of ordinary skill in the art is high.
Attie in its embodiment that includes polysorbate 80 at 0.24 grams, see above, results in 0.24/(56 + 0.19 + 3.03 + 0.24 + 100.80) = 0.15% on a w/w basis without reconstituting, the examiner noting that reconstituting is not required by claim 60 nor by claims from which it depends.
This is close to but not at least 0.2%.
Agarkhed teaches an optimization of polysorbate 80 concentration for thermal and photostability of a monoclonal antibody, Title, Abstract, and in the Abstract states, “This study demonstrates the importance of carefully choosing Polysorbate 80 concentration in protein formulations to prevent destabilizing effect of Polysorbate 80 on thermal and photostability.” Agarkhed teaches that the concentration of polysorbate 80 is a result-effective variable and amenable to routine optimization.
Nuijen, Abstract, teaches that for a different subject polypeptide, a study was done to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. This study included evaluating different concentrations of polysorbate 80 and citric acid when used with either mannitol or sucrose as bulking agents when preparing solutions for freeze-drying, and included studies upon reconstitution of lyophilized products. “It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a bulking agent were more stable compared to the products containing mannitol.” This further establishes that concentrations of polysorbate 80 and citric acid are known to be result-effective when considering solubility and stability of polypeptides that are to be lyophilized and then used as a therapeutic agent.
It would have been obvious to further evaluate polysorbate 80 concentrations, including those higher than the 0.24 g used in one embodiment by Attie, and arrive at a concentration that is at least 0.2%, by routine optimization. There would have been a reasonable expectation of success given the teachings of Agarkhed.
Accordingly, claim 65 is rejected as obvious under this section.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 The examiner notes that claim 1 does not require reconstitution to a liquid form before administering, and does not dispute that a lyophilized dry polypeptide preparation could be administered, as claim 1 seems to indicate, although from reading the prior art references the examiner opines that the normal approach to administering is as a liquid after reconstituting a dry product, such as a lyophilized polypeptide.