DETAILED CORRESPONDENCE
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 .
Claims 1-4, 29, and 30 are pending in the application and are being examined on the merits.
Applicant’s amendment to the claims, filed April 8, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks and declaration under 37 CFR 1.132 (hereafter “Mizumura Declaration”) filed April 8, 2026 in response to the non-final rejection mailed October 23, 2025 have been fully considered.
Claims 16, 17, 21-28 have been canceled and rejections previously applied to these claims are withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted April 9, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Claim Rejections - 35 USC § 112(a)
Claims 1-4, 29, and 30 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a Tachypleus tridentatus Factor C protein comprising the amino acid sequence of instant SEQ ID NO: 2 produced by recombinant expression from a HEK293 cell and containing (α-2,3)-linked terminal sialic acid that is subsequently treated with glycopeptidase F to remove N-linked sugars, does not reasonably provide enablement for all Factor C proteins encompassed by the claims. 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 test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The nature of the invention: According to the specification, “there has never been known a case where functional Factor C is produced using mammalian cells as host cells” (p. 5, paragraph [0011]) and “[a]n object of the present invention is to provide a novel recombinant horseshoe crab Factor C...another object of the present invention is to provide a reconstituted cascade reaction system which is not susceptible to reaction inhibition even in the presence of a salt (ion)" (p. 6, paragraphs [0014] and [0015]).
The breadth of the claims: Claim 1 (claims 2-4, 29, and 30 dependent therefrom) is drawn to a Factor C protein produced by recombinant expression from a Human Embryonic Kidney (HEK) 293 cell and having an enzymatic activity of Factor C, with the proviso that the Factor C protein does not contain a terminal linked sialic acid,
wherein the Factor C protein comprises an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2, and
wherein the enzymatic activity of Factor C is conversion by the Factor C of Factor B into activated Factor B in the presence of endotoxin.
The amount of direction provided by the inventor and The existence of working examples: The closest disclosed working example to the claimed invention is a Tachypleus tridentatus Factor C protein comprising the amino acid sequence of instant SEQ ID NO: 2 produced by recombinant expression from a HEK293 cell and containing (α-2,3)-linked terminal sialic acid (specification at pp. 79-80, paragraphs [0113] to [0115]; p. 99, paragraph [0154]) that is subsequently treated with glycopeptidase F to remove N-linked sugars (specification at pp. 95-97, paragraphs [0147] to [0149]). The instantly-filed Mizumura Declaration provides evidence that HEK293-produced Tachypleus tridentatus Factor C protein comprising the amino acid sequence of instant SEQ ID NO: 2 treated with glycopeptidase F to remove N-linked sugars has activity to convert Factor B into activated Factor B in the presence of endotoxin.
Other than HEK293-produced Tachypleus tridentatus Factor C protein comprising the amino acid sequence of instant SEQ ID NO: 2 treated with glycopeptidase F to remove N-linked sugars, the specification fails to provide any direction or guidance for recombinantly expressing a Factor C protein in a HEK29 cell such that the Factor C protein does not contain a terminal linked sialic acid and there is no evidence provided in the specification that a Factor C protein recombinantly expressed from a HEK293 cell and treated with glycopeptidase F to remove N-linked sugars has activity to convert Factor B into activated Factor B in the presence of endotoxin as required by the claim 1.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.” See MPEP § 2164.03.
Before the effective filing date, it was highly unpredictable as to whether or not a Factor C protein without a terminal linked sialic acid would have enzymatic activity to convert Factor B into activated Factor B in the presence of endotoxin. For example, the specification discloses that the recombinant Factor C derived from Carcinoscorpius rotundicauda and produced in insect cells is reported to exhibit no protease activity in response to endotoxin (specification at p. 87, paragraph [0132]). The amino acid sequence of Carcinoscorpius rotundicauda has 97% sequence identity to instant SEQ ID NO: 2, which is within the range of “an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2” in claim 1, and insect cells do not provide terminal sialylation (see, e.g., Geisler et al., Metabolic Engineering 14:642-652, 2012, particularly p. 642, column 2, bottom; cited on Form PTO-892 mailed October 23, 2025). Thus, one of skill in the art would recognize a high level of unpredictability that a recombinant Carcinoscorpius rotundicauda Factor C expressed from a HEK293 cell and having no terminal linked sialic acid would have enzymatic activity to convert Factor B into activated Factor B in the presence of endotoxin.
In view of the breadth and scope of the claims, the lack of guidance and working examples provided in the specification, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claims 1-4, 29, and 30 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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, at the time the application was filed, had possession of the claimed invention.
MPEP 2163.11.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include 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.”
For claims drawn to a genus, MPEP § 2163 states 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to MPEP 2163.11.A.3.(a).ii), “[s]atisfactory disclosure of a ‘representative number depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus... Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
Claim 1 (claims 2-4, 29, and 30 dependent therefrom) is drawn to a Factor C protein produced by recombinant expression from a Human Embryonic Kidney (HEK) 293 cell and having an enzymatic activity of Factor C, with the proviso that the Factor C protein does not contain a terminal linked sialic acid,
wherein the Factor C protein comprises an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2, and
wherein the enzymatic activity of Factor C is conversion by the Factor C of Factor B into activated Factor B in the presence of endotoxin.
The specification discloses a Tachypleus tridentatus Factor C protein comprising the amino acid sequence of instant SEQ ID NO: 2 produced by recombinant expression from a HEK293 cell containing (α-2,3)-linked terminal sialic acid (specification at pp. 79-80, paragraphs [0113] to [0115]; p. 99, paragraph [0154]) that is subsequently treated with glycopeptidase F to remove N-linked sugars (specification at pp. 95-97, paragraphs [0147] to [0149]).
Other than treatment with glycopeptidase F to remove N-linked sugars, the specification fails to provide any direction or guidance for recombinantly expressing a Factor C protein in a HEK29 cell such that the Factor C protein does not contain a terminal linked sialic acid and there is no evidence provided in the original application that a Factor C protein recombinantly expressed from a HEK293 cell and treated with glycopeptidase F to remove N-linked sugars has activity to convert Factor B into activated Factor B in the presence of endotoxin as required by the claim 1.
The unpredictability in the art is supported by the specification disclosing that the recombinant Factor C derived from Carcinoscorpius rotundicauda and produced in insect cells is reported to exhibit no protease activity in response to endotoxin (specification at p. 87, paragraph [0132]). The amino acid sequence of Carcinoscorpius rotundicauda has 97% sequence identity to instant SEQ ID NO: 2, which is within the range of “an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2” in claim 1, and, as described above, insect cells do not provide terminal sialylation (see, e.g., Geisler et al., Metabolic Engineering 14:642-652, 2012, particularly p. 642, column 2, bottom; cited on Form PTO-892 mailed October 2, 2025). Thus, one of skill in the art would recognize a high level of unpredictability that a recombinant Carcinoscorpius rotundicauda Factor C expressed from a HEK293 cell and having no terminal linked sialic acid would have enzymatic activity to convert Factor B into activated Factor B in the presence of endotoxin. In view of the evidence of record, before the effective filing date, one of skill in the art would have recognized a high level of unpredictability that a Factor C protein produced by recombinant expression from a HEK293 cell, wherein the Factor C protein comprises an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2 and does not contain a terminal sialic acid, would have enzymatic activity to convert Factor B into activated Factor B in the presence of endotoxin.
Given that the specification fails to disclose even a single representative species of the claimed invention and given the high level of unpredictability in the art, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that applicant was not in possession of the claimed genus of polypeptides. Therefore, the claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
RESPONSE TO REMARKS: In summary, applicant argues that before the effective filing date, it was well-known in the art that HEK 293 GnT1- cells enable the production of recombinant proteins lacking sialic acid and Dr. Mizumura’s post-filing experimental data and an example in US 2013/06564 published after the effective filing date (for clarity, it is noted that there is no apparent US 2013/06564 publication) provide evidence that Factor C expressed in HEK 293 GnT1- cells exhibits Factor C activity; and applicant argues the Mizumura Declaration demonstrates that Factor C produced by HEK293 cells and treated with glycopeptidase F retains Factor C activity. Thus, according to applicant, the specification enables and adequately describes the claimed invention.
Applicant’s argument is not found persuasive. In this case, applicant relies on post-filing evidence (i.e., Dr. Mizumura’s experimental data, an example in US 2013/06564, and the instantly-filed Mizumura Declaration) to support enablement and adequate written description. However, at least to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, the inventor was in possession of the invention. Applicant’s reliance on post-filing evidence fails to support the position that as of the filing date sought, the inventor was in possession of the invention. The only evidence proffered by applicant that was available at the time of filing are general teachings that HEK 293 GnT1- cells can be used for producing recombinant proteins with high mannose without sialic acid. However, the specification’s Example 4 (beginning at p. 85) and Example 10 (beginning at p. 97) suggest that Factor C without sialic acid and with high mannose such as Factor C produced in insect cells may have no Factor C activity (e.g., Carcinoscorpius rotundicauda Factor C). Thus, at the time of filing, one of skill in the art would have expected that Factor C produced using HEK 293 GnT1- cells may also lack Factor C activity. Moreover, as evidenced by Mizumura et al. (WO 2018/074498 A1; cited on the IDS filed February 10, 2025), at the time of filing, Limulus polyphemus Factor C, the amino acid sequence of which falls within “an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2,” could not be expressed using HEK293 cells. Thus, it follows that at the time of filing, one of skill in the art would have had no expectation that Limulus polyphemus Factor C could be produced using HEK 293 GnT1- cells. Here, the specification at best describes a plan for making a Factor C protein comprising an amino acid sequence having 90% or greater identity to the amino acid sequence of SEQ ID NO: 2 and produced by a HEK293 cell that does not contain a terminal linked sialic acid and then identifying those – if any – that have enzymatic activity to convert Factor B into activated Factor B in the presence of endotoxin. However, such a plan for obtaining the claimed invention is not sufficient to satisfy the written description requirement of 35 U.S.C. 112(a).
For these reasons, it is the examiner’s position that the specification fails to enable and adequately describe the claimed invention.
Conclusion
Status of the claims:
Claims 1-4, 16, 17, and 21-30 are pending.
Claims 1-4, 16, 17, and 21-30 are rejected.
THIS ACTION IS MADE FINAL. 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 DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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/David Steadman/Primary Examiner, Art Unit 1656
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