DETAILED CORRESPONDENCE
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 22, 2025 has been entered.
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, 16, 17, and 21-30 are pending in the application and are being examined on the merits.
Applicant’s amendment to the claims, filed September 22, 2025, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed September 22, 2025 in response to the advisory action mailed June 27, 2025 have been fully considered.
Rejections previously applied to claims 18-20 are withdrawn in view of applicant’s instant amendment to cancel these claims.
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 September 22, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-4, 16, 17, and 21-30 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“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: As amended, 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.
Claims 16, 17, and 21-23 are drawn to the Factor C protein according to claim 1, which exhibits higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, or 2.5 calcium chloride, respectively, as compared with a recombinant Factor C expressed in Sf9 cell as a host cell.
Claims 24-28 are drawn to the Factor C protein according to claim 1, which exhibits higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, or 2.5 calcium chloride, respectively, as compared with a Factor C derived from amebocyte of Tachypleus tridentatus.
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]).
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 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. There is also 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 exhibits the properties of higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cell as a host cell or as compared to a Factor C derived from amebocyte of Tachypleus tridentatus as required by claims 16, 17, and 21-28.
Rather, given that the specification discloses Tachypleus tridentatus Factor C produced in HEK293 cells contains (α-2,3)-linked terminal sialic acid (specification at p. 99, paragraph [0154]) and has higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cells or native Tachypleus tridentatus Factor C (Fig. 7), and Factor C produced in Sf9 cells or native Factor C has no or almost no (α-2,3)-linked terminal sialic acid (pp. 98-99, paragraph [0153]; Fig. 14), one would have found it highly unlikely that Tachypleus tridentatus Factor C produced in HEK293 cells and treated with glycopeptidase F would convert Factor B into activated Factor B in the presence of endotoxin and exhibit higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cell as a host cell or as compared to a Factor C derived from amebocyte of Tachypleus tridentatus.
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 the attached Form PTO-892). 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, 16, 17, and 21-30 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.
As amended, claim 1 (claims 2-4, 29, and 30 dependent therefrom) is drawn to a genus of Factor C proteins 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.
Claims 16, 17, and 21-23 are drawn to the Factor C protein according to claim 1, which exhibits higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, or 2.5 calcium chloride, respectively, as compared with a recombinant Factor C expressed in Sf9 cell as a host cell.
Claims 24-28 are drawn to the Factor C protein according to claim 1, which exhibits higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, or 2.5 calcium chloride, respectively, as compared with a Factor C derived from amebocyte of Tachypleus tridentatus.
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 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. There is also 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 exhibits the properties of higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cell as a host cell or as compared to a Factor C derived from amebocyte of Tachypleus tridentatus as required by claims 16, 17, and 21-28.
Rather, given that the specification discloses Tachypleus tridentatus Factor C produced in HEK293 cells contains (α-2,3)-linked terminal sialic acid (specification at p. 99, paragraph [0154]) and has higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cells or native Factor C (Fig. 7), and Factor C produced in Sf9 cells or native Factor C has no or almost no (α-2,3)-linked terminal sialic acid (pp. 98-99, paragraph [0153]; Fig. 14), one of skill in the art would have found it highly unlikely that Tachypleus tridentatus Factor C produced in HEK293 cells and treated with glycopeptidase F would convert Factor B into activated Factor B in the presence of endotoxin and exhibit higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cell as a host cell or as compared to a Factor C derived from amebocyte of Tachypleus tridentatus.
The unpredictability in the art is further 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 the attached Form PTO-892). 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 and even found it highly unlikely 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, much less to exhibit the properties of higher residual activity in the presence of 21 mM sodium citrate, 16 mM magnesium sulfate, 52 mM sodium hydrogencarbonate, 214 mM sodium chloride, and 2.5 calcium chloride as compared with a recombinant Factor C expressed in Sf9 cell as a host cell or as compared to a Factor C derived from amebocyte of Tachypleus tridentatus.
Given the high level of unpredictability in the art and because the specification fails to disclose even a single representative species of the claimed invention, 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.
Claim Rejections - 35 USC § 103
The rejection of claims 1-4, 16, and 17 under 35 U.S.C. 103 as being unpatentable over Ding et al. (US 5,858,706; cited on the IDS filed February 10, 2025; hereafter “Ding”) in view of Current Protocols in Molecular Biology (1993) 16.23.1-16.23.13, John Wiley and Sons, Inc., 2002 (cited on the IDS filed February 10, 2025; hereafter “Current Protocols”), and
the rejection of claim 20 under 35 U.S.C. 103 as being unpatentable over Ding in view of Current Protocols as applied to claims 1-4, 16, and 17 above, and further in view of Koshiba et al. (J. Biol. Chem. 282:3962-3967, 2007; cited on the IDS filed on February 10, 2025; hereafter “Koshiba”)
are withdrawn in view of the amendment to claim 1. The combination of cited prior art does not teach or suggest a Factor C protein produced by recombinant expression from a HEK293 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.
Claim Rejections - Double Patenting
The rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,040,254 B2 (cited on the IDS filed on February 10, 2025) in view of Ding, Current Protocols, and Koshiba,
the rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 11,162,949 B2 (cited on the attached Form PTO-892) in view of Ding, Current Protocols, and Koshiba,
the rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 7 of U.S. Patent No. 11,499,177 B2 (cited on the IDS filed on February 10, 2025) in view of Ding, Current Protocols, and Koshiba,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 1 of co-pending application 17/272,805 (reference application) in view of Ding, Current Protocols, and Koshiba,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 12 of co-pending application 17/449,736 (reference application) in view of Ding, Current Protocols, and Koshiba,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 3 of co-pending application 17/554,128 (reference application),
the provisional rejection of claim 19 on the ground of nonstatutory double patenting as being unpatentable over claim 3 of co-pending application 17/554,128 (reference application) in view of Ding,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claim 7 of co-pending application 18/045,705 (reference application) in view of Ding, Current Protocols, and Koshiba,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of co-pending application 19/048,080 (reference application),
the provisional rejection of claim 19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of co-pending application 19/048,080 (reference application) in view of Ding,
the provisional rejection of claims 1-4, 16, and 17 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of co-pending application 19/048,328 (reference application), and
the provisional rejection of claim 19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of co-pending application 19/048,328 (reference application) in view of Ding,
are withdrawn in view of the amendment to claim 1 to delete the alternative of “a Chinese Hamster Ovary (CHO) DG44 cell” and to require that the claimed Factor C protein “does not contain a terminal linked sialic acid.”
are withdrawn in view of the amendment to claim 1. The claims of the patent or reference application do not recite and the cited prior art does not teach or suggest a Factor C protein produced by recombinant expression from a HEK293 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.
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.
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