DETAILED OFFICE ACTION
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment to the claims, filed on November 14, 2025, is
acknowledged. This listing of the claims replaces all prior versions and listings of the
claims.
Claims 1-15, 17-21, and 28 are pending.
Claims 16 and 22-27 are cancelled.
Applicant’s remarks filed November 14, 2025 in response to the non-final rejection mailed August 14, 2025, are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In response to a requirement for restriction/election mailed March 28, 2025, applicant elected without traverse Group I, claims 1-15 and 17-19, and Species (B), the annexin is annexin V, in the reply filed May 27, 2025. Claims 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-15, 17-19, and 28 are under examination with claim 8 being examined only to the extent the claim reads on the elected subject matter.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 14, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner and those references therein have been indicated as such.
Claim Rejections - 35 USC § 101-Withdrawn
The rejection of claims 1-2 and 8 under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more is withdrawn in view of the Applicant’s persuasive argument that the Examiner failed to demonstrate the recited composition is not markedly different than its natural counterpart.
Claim Rejections - 35 USC § 112(b)-Withdrawn
The rejection of claims 4-6 under 35 U.S.C. 112(b) as being indefinite is withdrawn for reasons that follow.
The rejection of claim 4 (claims 5-6 dependent therefrom) for being indefinite because of the use of relative term “enhanced” in the phrase “enhanced ADPase activity” is withdrawn in view of Applicant’s argument that the recited term is a term of art understood by an ordinary artisan.
The rejection of claim 5 for being indefinite because the phrases “the apyrase is soluble CD39L3 in modified form wherein said modification consists of substitutions at amino acids positions 67 and 69” and “said substitutions are R67G and T69R”, respectively, are unclear because there are no sequences provided for CDL39L3 in the claims to which the substitutions can be related is withdrawn in view of Applicant’s amendment to claim 5 to relate the substitutions of positions 67 and 69 to the sequence of SEQ ID NO: 23. The rejection of claim 6 is maintained because the claim was not modified and does not depend upon the modifications made to claim 5.
Claim Rejections - 35 USC § 112(b)-New
Claims 6-7 and 18-19 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 6 (claim 7 dependent therefrom) is rejected as indefinite because the claim recites the term "said substitutions" in line 1 which lacks antecedence. Claim 6 depends from claims 1 and 4, which do not recite “substitutions.” Since claim 6 depends upon claim 4 which further depends upon claim 1, there is insufficient antecedent basis for this limitation and therefore the phrase "said substitutions" lacks antecedence. For the purpose of compact prosecution, claim 6 is interpreted as “The composition of claim 4 wherein said modification comprises R67G and T69R substitutions relative to SEQ ID NO: 23.”
Claim 18 (claim 19 dependent therefrom) is rejected as indefinite because the claim recites “covalently coupled through a linker peptide” in the phrase "a fusion protein that comprises apyrase and annexin covalently coupled through a linker peptide" in lines 1-2 of the claim which lacks antecedence. Since claim 18 depends upon claim 17, claim 17 depends upon claim 15, and claim 15 depends upon claim 3, and none of claims 3, 15, and 17 recite the phrase “linker peptide,” there is insufficient antecedent basis for the limitation “covalently coupled through a linker peptide” in claim 18.
Claim Rejections - 35 USC § 112(a)-Withdrawn
The rejection of claims 1-15 and 17-21 under 35 U.S.C. 112(a) for failing to comply with the written description requirement is withdrawn in view of the persuasive argument from the Applicant regarding the well-known status of the apyrase art at the time of filing.
The rejection of claims 1-15 and 17-21 under 35 U.S.C. 112(a) because the specification fails to comply with the enablement requirement is withdrawn in view of the persuasive argument from the Applicant regarding the well-known status of the apyrase art at the time of filing which would not lead to undue experimentation for an ordinary artisan to make and use the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
Claims 1, 4-8, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Moeckel et al. (Sci. Transl. Med., published August 6, 2014, Vol. 6, No. 248, p. 1-10; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Moeckel”) in view of Cederholm et al. (US 2008/0044404 A1; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Cederholm”) as evidenced by Koopman et al. (Blood, published September 1, 1994, Vol. 84, No. 5, p. 1415-1420; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Koopman”) and Chen et al. (US 8,535,662 B2; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Chen’662”). Claim 28 is included in the rejection, which is necessitated by Applicants addition of the claim.
Regarding claims 1, 4-8, and 28, Moeckel teaches the use of the apyrase variant, APT102, to treat thrombosis and limit reperfusion injury without increasing bleeding risk (Title; Abstract; p. 1, col 1, para 3 – p. 2, col 2, para 2; p. 5, col 2, para 1; p. 7 col 2, para 2-3). The apyrase is a variant of soluble domain of CD39L3 wherein the protein comprises R67G and T69R mutations (termed “APT102”) that exhibits four-fold increased ADPase activity as compared to a non-mutated control (e.g., APT101) (Abstract; p. 2, col 2, para 2; p. 3, col 1, para 2; Meeting claim limitations of claim 1 and dependent claims 4-7). The current American Heart Association and American College of Cariology standard treatment acute myocardial infarction comprises administration of clopidogrel and aspirin (p. 1, col 1, para 1). Moeckel teaches treating a dog model of thrombotic occlusion of a coronary artery with high dose APT102 prevents coronary thrombotic reocculsion, clopidogrel and aspirin reoccluded in all subjects (Table 1; Figure 3; p. 4, col 1, para 2 – p. 4, col 2, para 1).
Moeckel does not teach an annexin.
Cederholm teaches the use of Annexin V, or fragments thereof, to treat or prevent thrombosis (Abstract; para [0014]; claims 1 and 4). Cederholm also teaches wherein Annexin V binds to activated platelets and binds negatively charged phospholipids (para [0005-0006]; Meeting claim limitations of independent claim 1 and dependent claim 8).
Evidentiary reference Koopman is cited to show that Annexin V inherently binds the negatively charged phosphatidylserine (p. 1415, col 1, para 3).
Evidentiary reference Chen’662 is cited to show that the amino acid sequence of APT102 (taught by Moeckel) is identical to the sequence of instant SEQ ID NO: 2 (meeting claim limitations of claim 8). Since Chen’662 teaches the sequence of soluble CD39L3 R67G and T69R (SEQ ID NO: 2; Claim 6) that is identical to instant SEQ ID NO: 2, the soluble CD39L3 R67G and T69R variant taught by Moeckel termed APT102 therefore inherently comprises the sequence of instant SEQ ID NO: 2.
In view of the combined teachings of Moeckel and Cederholm, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the use of APT102 apyrase to treat thrombosis without increasing bleeding risk taught by Moeckel such that the treatment also comprises the Annexin V taught by Cederholm, thereby arriving at the invention of claim 1, 4-8, and 28.
According to MPEP 2144.06.I, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” Therefore, since both apyrase and annexin V taught by Moeckel and Cederholm, respectively, are effective treatments for thrombosis, it would have been obvious for an ordinary artisan to combine an APT102 apyrase taught by Moeckel and annexin V taught by Cederholm into one composition in order to treat thrombosis.
Consequently, the invention of claims 1, 4-8, and 28 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 2-3 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm as applied to claims 1, 4-8, and 28 above, and further in view of Tanaka et al. (Biochemistry, published 1996, Vol. 35, p. 922-929; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Tanaka”) and Chen et al. (Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants, Blood, published May 15, 2005, Vol. 105, No. 10, p. 3902-3909; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Chen’05”) as evidenced by Koopman and Chen'662.
Regarding claims 2-3 and 9, the relevant teachings of Moeckel, Cederholm, and evidentiary references Koopman and Chen'662 as applied to claims 1, 4-8, and 28 are discussed above and incorporated herein.
Regarding claim 2, the combination of Moeckel and Cederholm does not teach or suggest wherein the linker peptide comprise 3-30 or 15-25 amino acids.
Tanaka teaches a composition wherein a protein-based thrombolytic therapeutic conjugated to annexin V as a means to better target the therapeutic to phospholipid-containing thrombi (Abstract; p. 922, col 1, para 1; p. 923, col 1, para 2). The Annexin V-conjugated therapeutic exhibits 3-4 times more activity in vivo than the non-conjugated therapeutic in a rat pulmonary embolism model (Abstract; p. 927, col 1, para 2; p. 928, col 1, para 2). The annexin V-conjugated protein shows the same binding affinity for phosphatidylserine-containing membranes as annexin V alone (Abstract).
Chen’05 teaches a fusion protein comprising annexin V (ANV) to the Kunitz-type protease inhibitor (KPI) domain of tick anticoagulant protein (TAP) and use thereof as an antithrombic agent that targets phosphatidyl-serine in at developing thrombin (Abstract; Figure 1; p. 3904, col 2, para 3; p. 3908, col 1, para 1). Chen teaches fusing Annexin V to the C-terminus of TAP via a glycine-serine linker to produce the TAP-ANV fusion protein (Figure 1). Administering TAP-ANV prolongs the time to occlusion in a mouse thrombosis model while non-fusion administration of TAP and ANV does not (Table 3; p. 3906, col 2, para 2).
In view of the combined teachings of Moeckel, Cederholm, Tanaka, and Chen’05, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to conjugate and fuse annexin V with a glycine-serine peptide linker to the C-terminus of APT102 apyrase in order to better target the therapeutic to phospholipid-containing thrombi and increase therapeutic activity. A fusion of one APT102 to annexin V would constitute an equimolar ratio.
An ordinary artisan would have been motivated to conjugate and fuse APT102 apyrase with Annexin V with a glycine-serine linker in order to better target the therapeutic to phospholipid-containing thrombin and increase therapeutic activity. This is because Tanaka teaches conjugating annexin V to better target a protein-based thrombolytic therapeutic to phospholipid-containing thrombi which results in 3-4 increased therapeutic activity. Furthermore, Chen’05 taught fusing annexin V to an antithrombic via a glycine-serine peptide linker and the fusion improved the time to conclusion as compared to control or administration for the individual components of the fusion protein.
An ordinary artisan would have had a reasonable expectation of success of fusing APT102 apyrase with annexin V with a glycine-serine peptide linker because Chen’05 taught fusing annexin V to a protein-based antithrombotic protein and the fusion.
Consequently, the invention of claims 2-3 and 9 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm, Tanaka, and Chen’05 as applied to claims 1-9 and 28 above, and in further view of Karpatkin et al. (US 2011/0045008 A1; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Karpatkin”) as evidenced by Koopman, Chen’662, and Kavoosi et al. (Biotechnology and Bioengineering, published October 15, 2007, Vol. 98, No. 3, p. 599-610; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Kavoosi”).
Regarding claims 10-12, the relevant teachings of Moeckel, Cederholm, Tanaka, Chen’05, and evidentiary references Koopman and Chen'662 as applied to claims 1-9 and 28 are discussed above and incorporated herein.
The combination of Moeckel, Cederholm, Tanaka, and Chen’05 does no teach or suggest wherein the linker peptide comprises 3-30 or 15-25 amino acids and the linker peptide is resistant to hydrolysis in plasma and/or in cell culture supernatant.
Karpatkin teaches a fusion protein comprising a thrombin-specific targeting agent comprising a linker peptide with a glycine and serine rich linker such as a linker with an amino acid sequence of (GSTSG)3SGSGI (SEQ ID NO: 16; Claim 8; para [0050, 0117]).
In view of the combined teachings of Moeckel, Cederholm, Tanaka, Chen’05, and Karpatkin, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the glycine-serine linker taught by Chen’05 for the glycine- and serine-rich linker taught by Karpatkin comprising an amino acid sequence of (GSTSG)3SGSGI, thereby arriving at the invention of claims 10-11.
An ordinary artisan would have been motivated to substitute the glycine-serine linker taught by Chen’05 for the glycine- and serine-rich linker taught by Karpatkin comprising an amino acid sequence of (GSTSG)3SGSGI because a simple substitution of a glycine-serine peptide linker for a glycine- and serine-rich linker would be expected to yield predictable results and be considered obvious.
An ordinary artisan would have had a reasonable expectation of success of substituting the glycine-serine linker taught by Chen’05 for the glycine- and serine-rich linker comprising an amino acid sequence of (GSTSG)3SGSGI because Karpatkin already taught the linker in a fusion protein targeting thrombi.
Regarding claim 12, the combination of Moeckel, Cederholm, Tanaka, Chen’05, and Karpatkin do not explicitly teach a linker peptide that is resistant to hydrolysis in plasma and/or in cell culture supernatant.
Evidentiary reference Kavoosi is cited to show that the glycine- and serine-rich (GSTSG)3SGSGI linker taught Karpatkin is inherently resistant to hydrolysis. This is because Kavoosi teaches glycine- and serine-rich linkers are resistant to proteolysis within a host (Abstract; p. 600, col 1, para 4).
Consequently, the invention of claims 10-12 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim Rejections - 35 USC § 103-Withdrawn
The rejection of claim 13 under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm, Tanaka, Chen’05, and Karpatkin as applied to claims 1-12 and 28 above, and further in view of Chen et al. (Advanced Drug Delivery, published 2013, Vol. 65, No. 10, p. 1357-1369; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Chen’13”) as evidenced by Koopman, Chen’662, and Kavoosi is withdrawn after second consideration by the Examiner.
The rejection of claim 14 under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm, Tanaka, Chen’05, Karpatkin, and Chen’13 as applied to claims 1-13 and 28 above, and further in view of GenPept Accession Number 1ANW_A (version published October 10, 2012; cited on the Form PTO-892 mailed August 14, 2025; hereafter “1ANW_A”) as evidenced by Koopman, Chen’662, and Kavoosi is withdrawn after second consideration by the Examiner.
The rejection of claims 15 and 17-19 under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm, Tanaka, Chen’05, Karpatkin, Chen’13, and 1ANW_A as applied to claims 1-14 and 28 above, and further in view of Odani et al. (US 2009/0155277 A1; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Odani”) as evidenced by Koopman, Chen’662, Kavoosi is withdrawn after second consideration by the Examiner.
Claim Rejections - 35 USC § 103-New
Claims 15 and 17-19 are newly rejected under 35 U.S.C. 103 as being unpatentable over Moeckel in view of Cederholm, Tanaka, Chen’05, and Karpatkin, as applied to claims 1-12 and 28 above, and further in view of Odani et al. (US 2009/0155277 A1; cited on the Form PTO-892 mailed August 14, 2025; hereafter “Odani”) and as evidenced by Koopman, Chen’662, Kavoosi.
Regarding claims 15 and 17-19, the relevant teachings of Moeckel, Cederholm, Tanaka, Chen’05, Karpatkin, and evidentiary references Koopman and Chen'662 as applied to claims 1-12 and 28 are discussed above and incorporated herein.
Moeckel further teaches a method of expressing and recovering APT102 protein using expression plasmids transfected into 293T cells (Supplemental p. 2, para 3 – p. 3, para 1).
The combination of Moeckel, Cederholm, Tanaka, Chen’05, and Karpatkin, does not explicitly teach a nucleic acid that encodes apyrase covalently coupled to annexin, a recombinant cell hosts or vectors that encodes said nucleic acid, and a method of producing a covalently coupled apyrase to annexin via a peptide linker.
Odani teaches all codons for each amino acid (para [0112]).
In view of the combined teachings of Moeckel, Cederholm, Tanaka, Chen’05, Karpatkin, and Odani, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to convert the amino acid sequence encoding the (APT102)-((GSTSG)3SGATI)-(annexin V) modified fusion protein to a nucleic acid sequence as well as incorporating said nucleic acid sequence into the expression vector transfected into host cells taught by Moeckel in order to express and recover the fusion protein. Thereby, arriving at the invention of claims 15 and 17-19.
An ordinary artisan would have been motivated to convert the amino acid sequence encoding the (APT102)-((GSTSG)3SGATI)-(annexin V) modified fusion protein to a nucleic acid sequence as well as incorporating said nucleic acid sequence into the expression vector transfected into host cells taught by Moeckel in order to express and recover the fusion protein.
An ordinary artisan would have had a reasonable expectation of success of converting the amino acid sequence encoding the (APT102)-((GSTSG)3SGATI)-(annexin V) modified fusion protein to a nucleic acid sequence because Odani teaches all codons for each amino acid. An ordinary artisan would have had a reasonable expectation of success incorporating said nucleic acid sequence into the expression vector transfected into host cells taught in order to express and recover the fusion protein because Moeckel already taught incorporating a APT102 into a vector transfected into cells as well as expressing and recovering the protein.
Consequently, the invention of claim 15 and 17-19 would have been obvious to one of ordinary skill in the art before the effective filing date.
Applicant’s Arguments and Examiner’s Response
ARGUMENT: Applicant argues the claimed composition provides unexpected properties that were not recognized or predicted in the cited prior art.
According to applicant, Example 4 and Figure 3 of the present application provide evidence of the synergistic effect of the combination of an apyrase (APT102) and an annexin that binds phosphatidyl serine(PS) on the surface of activated platelets (annexin V) on inhibition of thrombin generation. Applicant argues the claimed configuration provides an unexpected synergistic technical effect. None of the cited prior art teach or suggest that
patients with a combination of an apyrase and an annexin or that the combination would result in synergistic activity.
RESPONSE TO REMARKS: The Examiner does not find these arguments and conclusion of unexpected results persuasive. According to MPEP 716.02(d), unexpected results must be commensurate in scope with the claimed invention. “Commensurate in scope” means that the evidence provides a reasonable basis for concluding that the untested embodiments encompassed by the claims would behave in the same manner as the tested embodiments. See In re Lindner, 457 F.2d 506, 508 (CCPA 1972). Applicant’s results presented in their argument are based on a composition of APT102 and Annexin V, however, other than claim 14, there is no claim to a composition of APT102 and Annexin V. While nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range (MPEP 716.02(d).I), there is no evidence of record that the untested embodiments encompassed by the claims would behave in the same manner as the tested embodiments. In this case, applicant’s results are not commensurate in scope with the claimed invention and consequently fail to rebut a prima facie case of obviousness.
According to MPEP 716.02(e), applicant’s results must be compared with the closest prior art, which appears to be Tanaka or Chen’05. However, applicant’s results do not appear to be a comparison with the closest prior art. Moreover, Tanaka demonstrates that fusion of annexin V to a thrombolytic therapeutic protein increases its activity 3-4 fold (Abstract; p. 927, col 1, para 2; p. 928, col 1, para 2). Thus, it would not have been unexpected to an ordinary artisan that fusion of annexin V to a thrombus-related therapeutic protein, like APT-102, would result in a synergistic enhancement in its activity. Therefore, the evidence of unexpected results fails to rebut the prima facie case of obviousness.
Allowable Subject Matter
Claims 13-14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
As amended, claim 13 is drawn to a composition comprising apyrase and annexin covalently coupled through a linker peptide to form a fusion protein wherein the linker peptide has the amino acid sequence of SEQ ID NO: 6 and claim 14 is drawn to wherein the fusion protein has the amino acid sequence of SEQ ID NO: 10.
Moeckel teaches the use of the apyrase variant, APT102, to treat thrombosis and limit reperfusion injury without increasing bleeding risk (Title; Abstract; p. 1, col 1, para 3 – p. 2, col 2, para 2; p. 5, col 2, para 1; p. 7 col 2, para 2-3). Cederholm teaches the use of Annexin V, or fragments thereof, to treat or prevent thrombosis (Abstract; para [0014]; claims 1 and 4). As described above, the combination of Moeckel, Cederholm, Tanaka, Chen’05, and Karpatkin suggests fusion protein comprising APT102 linked to Annexin V via a linker peptide. The prior art of record does not teach or suggest a composition comprising apyrase and annexin covalently coupled through a linker peptide to form a fusion protein wherein the linker peptide has the amino acid sequence of SEQ ID NO: 6 nor wherein the fusion protein has the amino acid sequence of SEQ ID NO: 10. As such, the compositions comprising the apyrase and annexin fusions of claims 13-14 are allowable over the prior art of record.
Conclusion
No claims are currently allowed for the reasons as stated above. Applicants must
respond to the objections/rejections in this Office action to be fully responsive in
prosecution.
The instant Office Action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SCOTT E. MULDER whose telephone number is (571)272-2372. The examiner can normally be reached Monday - Friday 7:30 AM - 3:30 PM.
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/SCOTT E. MULDER/Examiner, Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
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