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 .
Detailed Action
This action is in response to the papers filed December 24, 2025.
Amendments to Specification
The substitute specification filed 12/24/2025 has not been entered because it does not conform to 37 CFR 1.125(b) and (c), for the following reasons:
In this case, 37 CFR 1.125(b) and (c) requires a substitute specification must be submitted with markings showing all the changes relative to the immediate prior version of the specification of record. However, the substitute specification filed 12/24/2025 does not include the previous amendment to the specification filed on 06/06/2022, which introduces a new paragraph on page 1 titled CROSS REFERENCE TO RELATED APPLICATIONS. Accordingly, the amendments to the specification filed 12/24/2025 were not made relative to the immediate prior version of the specification of record, as required by 37 CFR 1.125(b) and (c).
For these reasons, the substitute specification filed 12/24/2025 has not been entered. Accordingly, given non-entry of the substitute specification, the previous objections to the specification for incompliance with the sequence rules and other minor informalities are maintained. Please resubmit the substitute specification with the inclusion of the previous amendment to the specification filed on 06/06/2022. Appropriate action is required in response to this action. This objection will not be held in abeyance.
Claim Amendments
Applicant’s amendment to the claims filed 12/24/2025 is acknowledged.
Claims 1, 3-14, 17-21 are pending.
Claims 18-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1, 3-14 and 17 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the present application. See the Requirement for Restriction/Election mailed 04/18/2025.
In the reply filed 06/13/2025, applicant elected without traverse the invention of Group 1, drawn to an isolated recombinant soluble endothelial cell protein C receptor (r-sEPCR), and a nucleic acid encoding thereof.
In the reply filed 12/24/2025, applicant completed the restriction/election requirements regarding the “hemostatic disorder” and “antifibrinolytic protein.” In particular, applicant elected hemophilia A and thrombomodulin. See page 7 of applicant’s reply filed 12/24/2025.
Claims 18-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/13/2025.
Priority
The instant application 17/782,924 was filed on 06/06/2022. This application is a national stage of international application PCT/EP2020/084333 filed 12/02/2020, claiming priority based on European patent application EP19214319.6 filed 12/08/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 08/27/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Allowable Subject Matter
Claim 7 is 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. In this case, the prior art does not teach or fairly suggest the recombinant r-sEPCR polypeptides comprising the amino acid sequence according to SEQ ID NO: 7 or 8, as claimed.
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 5-6 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.
This rejection is newly applied, necessitated by amendment.
Claims 5 and 6 both recite that the haemostatic agent comprises “a his-labelled heterologous peptide.” This limitation is found to be new matter. In this case, the specification as originally filed does not describe a “his-label” or a “his-labelled heterologous peptide.” Rather, the specification as originally filed describes attaching a “his-tag” or “polyhistidine tag” to haemostatic agent, which is defined to mean “a string of histidine residues at either the N- or C-terminus of a recombinant protein” (pg. 6). The new recitation of a “his-labelled heterologous peptide” is considered to be materially different in scope than the described “his-tag” or “polyhistidine tag” found in the original disclosure. For example, a “his-labelled heterologous peptide” may not comprise “a string of histidine residues” but rather a single histidine residue or another “his” molecule, e.g., a histatin. Please further note that the terms “his-label” and “his-labelled heterologous peptide” are neither defined nor found in the original disclosure.
For these reasons, absent evidence to the contrary, claims 5 and 6 are found to include new matter. Please note that using the terms “his-tag” or “polyhistidine tag” in the claims would not raise an issue under 35 U.S.C. 112(b), as previously raised regarding the term “Tag” and trademarks, because the terms “his-tag” or “polyhistidine tag” are clearly defined on page 6 of the specification.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 8-10, 14 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2012/178693 A1 to Light et al.
This rejection is newly applied, necessitated by amendment.
Claim 1 recites a haemostatic agent comprising an isolated recombinant soluble endothelial cell protein C receptor (r-sEPCR), wherein the agent comprises the sequence according to SEQ ID NO: 2 or 4 and a heterologous peptide.
Light discloses fusion proteins that are useful for treating hemorrhages and bleeding disorders, such as hemophilia A, comprising a thrombin-binding domain, a linker, and a FVII-binding domain (par. 2, 17), wherein the FVII-binding domain is the FVII-binding domain from EPCR (par. 4, 6, 19). Light provides an amino acid sequence for the EPCR FVII-binding domain according to SEQ ID NO: 31, which is a fragment of SEQ ID NO: 2 of the instant application:
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Accordingly, Light is found to teach a recombinant polypeptide comprising a soluble EPCR domain and a heterologous peptide domain.
Light further provides exemplary fusion proteins, including a plurality of fusion proteins comprising a soluble EPCR domain and a heterologous peptide domain, e.g., sEPCR-TMcE56 (SEQ ID NO: 53), sEPCR-HCIIABE (SEQ ID NO: 72), sEPCR-PAR1 (SEQ ID NO: 74), sEPCR-FVIIIABE (SEQ ID NO: 76), sEPCR-OPN (SEQ ID NO: 78), sEPCR-HIR (SEQ ID NO: 80), sEPCR-FVABE (SEQ ID NO: 82), and sEPCR-Apple1 (SEQ ID NO: 84). See pages 9-16.
The fusion proteins comprising a soluble EPCR domain and a heterologous peptide domain, as found in Light, further comprise the sequence according to SEQ ID NO: 2 of the instant application. For example, see the alignment between SEQ ID NO: 2 of the instant application (Qy) and Light’s sEPCR-TMcE56 fusion construct according to SEQ ID NO: 53 (Db):
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For these reasons, Light anticipates claim 1.
Light further discloses DNA sequences encoding the fusion proteins, which are inserted into recombinant vectors or expression vectors (par. 25-27), as claimed in claims 8-9.
Light further teaches a pharmaceutical composition comprising the fusion protein and a biologically acceptable carrier (par. 52-53), as claimed in claim 17.
Regarding dependent claim 4, Light discloses a linker between the soluble EPCR domain and the heterologous peptide domain. See, e.g., paragraph 2, and exemplary fusion protein sequences.
Regarding dependent claim 10, Light teaches that the recombinant vector is an integrating vector or autonomously replicating vector, such as a plasmid (par. 25). Light also teaches that mammalian cells are transfected with the coding sequences via retroviral delivery (par. 31), which means that the recombinant vector is a retroviral vector.
Regarding dependent claim 14, Light teaches that the expression vector comprises a promoter capable of directing the transcription of a cloned gene or cDNA. Exemplary constitutive promoters are provided, such as SV40 promoter and CMV promoter. See paragraph 27.
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over US 2012/178693 A1 to Light et al., as applied to claims 1, 4, 8-10, 14 and 17 above; in view of US 2018/0244730 A1 to Howarth, Mark.
This rejection is newly applied, necessitated by amendment.
Dependent claim 3 further recites that the heterologous peptide comprises the sequence according to SEQ ID NO: 14. As described on page 16 of applicant’s specification, the amino acid sequence according to SEQ ID NO: 14 refers to SnoopTag® (US Registration No. 1692629). Light does not teach or fairly suggest that the fusion proteins further comprise a SnoopTag® or the amino acid sequence according to SEQ ID NO: 14, as claimed.
However, Howarth is relevant prior art for teaching a means of fusing a first protein to a second protein using a pair of peptide linkers which react to form an isopeptide bond that links said first protein to said second protein to form a fusion construct (Abstract; par. 14, 35, 270; Figure 1). In particular, peptide linkers are “SnoopTag” and “SnoopCatcher” (par. 35, 270; Figure 1). Howarth’s methods advantageously provide a modular and high yielding approach of fusing proteins, where the fused proteins are joined by an irreversible linkage, i.e., an isopeptide bond, without reliance on the use of unnatural amino acids, post-translational modifications, or purification of intermediates. See, e.g., par. 3-6, 14.
Howarth further teaches that the linker peptide or “SnoopTag” has the sequence according to SEQ ID NO: 1 (par. 270), which is identical to SEQ ID NO: 14 of the instant application:
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Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Light by further including the amino acid sequence according to SEQ ID NO: 14 (SnoopTag®), as found in Howarth, with a reasonable expectation of success because Light teaches the fusion of sEPCR to other proteins (e.g., pg. 9-16), and Howarth’s methods using “SnoopTag” and “SnoopCatcher” advantageously provide a modular and high yielding approach of fusing proteins via an irreversible linkage, i.e., an isopeptide bond, without reliance on the use of unnatural amino acids, post-translational modifications, or purification of intermediates. See, e.g., Howarth, paragraphs 3-6, 14.
For these reasons, dependent claim 3 would have been prima facie obvious over the prior art.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/178693 A1 to Light et al., as applied to claims 1, 4, 8-10, 14 and 17 above; in view of Loughran et al. (2006) “Modified His-tag fusion vector for enhanced protein purification by immobilized metal affinity chromatography” Analytical biochemistry, 355:148-150.
This rejection is newly applied, necessitated by amendment.
Dependent claim 5 further recites that a his-labelled heterologous peptide is fused to the C-terminal end of the r-sEPCR via a peptide linker.
Light discloses that a 6x His tag may be attached to the C-terminus of the fusion protein, which is useful for detection, purification, or identification of the fusion protein (see par. 51). The fusion protein may also comprise a linker (par. 7-8). See also paragraph 73 regarding the orientation of the soluble EPCR domain relative to the heterologous peptide domain.
However, Light does not teach or fairly suggest that the His tag is attached to the fusion protein via a peptide linker.
Loughran is relevant prior art for teaching affinity tags, such as his-tags, for purification of recombinant proteins. In particular, Loughran teaches that one relatively common reason for the failure to purify his-tagged proteins is due to inaccessibility of the his-tag as a result of protein folding or tightly bound via interaction with adjacent residues on the protein’s surface. To overcome this problem, Loughran teaches distancing the his-tag from the rest of the protein by inserting a spacer or linker peptide between the two domains. To this end, Loughran engineered a glycine-serine linker between the his-tag and the recombinant protein sequence so as to spatially separate them from one another. See pages 148-149, and fig. 1.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Light by including a peptide linker between the his-tag and the protein, as taught by Loughran, with a reasonable expectation of success because a peptide linker improves accessibility of the his-tag for purification of the recombinant protein.
For these reasons, dependent claim 5 would have been prima facie obvious over the prior art.
Regarding dependent claim 6, Loughran teaches that the peptide linker has the sequence according to SEQ ID NO: 10, i.e., to (GGGGS)n. See fig. 1.
Claims 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/178693 A1 to Light et al., as applied to claims 1, 4, 8-10, 14 and 17 above; in view of Mingozzi et al. (2011) “Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges” Nature reviews genetics, 12(5), 341-355.
This rejection is newly applied, necessitated by amendment.
Regarding dependent claim 11, Light does not teach or fairly suggest that the expression vector is an AAV vector, as claimed.
Mingozzi is relevant prior art for teaching that AAV vectors have been extensively used for in vivo gene transfer, capable of achieving long-term transgene expression and targeting various tissues, including the liver, skeletal muscle, cardiac muscle and cells in the central nervous system. See, e.g., Abstract and Box 2.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Light by using an AAV vector as the expression vector, as taught by Mingozzi, with a reasonable expectation of success because AAV vectors have been extensively used for in vivo gene transfer, capable of achieving long-term transgene expression and targeting various tissues, including the liver, skeletal muscle, cardiac muscle and cells in the central nervous system. See, e.g., Abstract and Box 2 of Mingozzi.
Mingozzi further various AAV serotypes, including AAV1, AAV2, AAVrh10, AAV6 and AAV8 (see, e.g., Table 1), as claimed in claim 11.
For these reasons, dependent claim 11 would have been prima facie obvious over the prior art.
Regarding dependent claims 12-13, Mingozzi further teaches that the AAV vectors are flanked by ITR sequences, e.g., AAV2 ITRs. See, e.g., Figure 2.
Response to Arguments
Applicant’s remarks filed 12/24/2025 have been carefully considered, but are not found persuasive for the following reasons:
Applicant argues that Light describes fusion protein comprising sEPCR fragments, but the claimed invention uses the entire sEPCR molecule. See page 11 of applicant’s reply.
The argument is not persuasive because the fusion proteins found in Light comprise the amino acid sequence according to SEQ ID NO: 2, as instantly claimed.
Applicant argues that the claims differ from the cited references because said cited references do not teach that sEPCR-mediated inhibition of activated protein C anticoagulant activity can be utilized to promote thrombin generation and restore haemostasis. See pages 11-12 of applicant’s reply.
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this case, the instant claims do not recite a limitation of inhibiting activated protein C anticoagulant activity, promoting thrombin generation, or restoring haemostasis. Furthermore, the claims under examination are directed to a product and not a method or process.
The remainder of applicant’s arguments are found to be sufficiently addressed or otherwise moot in view of the new grounds of rejection set forth in this action.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631