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 application is a 371 of PCT/EP2023/068246.
The amendment filed on December 30, 2024 has been entered.
Status of Claims
Claims 1-16 are pending.
Claims 1-16 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 30, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pages 20-21). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 1-16 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.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' The claims are directed to a complex comprising (A) any protease, any elastase, any serine protease, any cysteine protease, any threonine protease, any aspartic proteinase, any glutamic protease, any metalloprotease, or any asparagine peptide lyase and (B) any negatively charged polysaccharide or any glycosaminoglycan (GAG), to treat, prevent, or ameliorate any extracellular histone-mediated diseases or disorders, any immunothrombosis related diseases, disorders, or trauma, or the disorders recited in claim 11. Therefore, the claims are drawn to a genus of complexes having unknown structure to treat, prevent, or ameliorate a genus of disorders.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory 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 recitations of “protease”, “elastase”, “serine protease”, “cysteine protease”, “threonine protease”, “aspartic proteinase”, “glutamic protease”, “metalloprotease”, “asparagine peptide lyase”, “negatively charged polysaccharide”, “glycosaminoglycan” to treat, prevent, or ameliorate any extracellular histone-mediated diseases or disorders, any immunothrombosis related diseases, disorders, or trauma, or the disorders recited in claim 11 fail to provide a sufficient description of the genus as it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
The prior art discloses a complex comprising (A) activated Protein C and (B) heparin to treat hemostatic disorders, such as sepsis, see Hirahara (EP 0 326 014 – form PTO-1449) and Wildhagen (Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014 Feb 13;123(7):1098-101 – form PTO-1449). However, the claimed genus of complex to treat, prevent, or ameliorate any extracellular histone-mediated diseases or disorders, any immunothrombosis related diseases, disorders, or trauma, or the disorders recited in claim 11 was not known.
The specification is limited to a complex comprising (A) activated Protein C or neutrophil elastase and (B) heparin, to decrease cytotoxic activity of histones. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or 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.” In view of the widely variant species encompassed by the genus, the two examples described above are not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
The claimed invention requires a defined set of protease and negatively charged polysaccharides to treat, prevent, or ameliorate a plethora of disorders or diseases. Although the specification discloses exemplary protease and negatively charged polysaccharides, a “laundry list” disclosure of every possible moiety does not necessarily constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species, see Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) or MPEP 2163. While the exemplary protease and negatively charged polysaccharides were known in the art, this knowledge alone would not allow one level of skill in the art to immediately envisage the claimed genus. Therefore, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which combination of protease and negatively charged polysaccharides to form a complex to treat, prevent, or ameliorate a plethora of disorders or diseases
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1-16.
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 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, 3-5, 8-9, and 15-16is/are rejected under 35 U.S.C. 102(a)(1) and/or as being anticipated by Hirahara (EP 0 326 014 – form PTO-1449).
Regarding claims 1, 3-5, 8, and 15, Hirahara discloses a formulation comprising (A) heparin, a negatively charged polysaccharide comprising of variably sulphated repeating disaccharide units belonging to glycosaminoglycan (GAG) family, and (B) activated protein C, a serine protease for treating hemostatic disorders, which are driven by histones (Example 1 and claim 1). The formulation of Hirahara reads on a complex because heparin is bound to activated Protein C by van der Waals forces, electrostatic forces, or ionic forces, between the negatively charged heparin and positively charged Lys and Arg residues on Protein C, as evidenced by the instant specification at page 21, lines 18-24 and Yu (see page 4, 1st full paragraph. Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins—An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic. Front. Mol. Biosci. 7:628551. (2021) – form PTO-892).
Regarding claims 9 and 16, Hirahara discloses a pharmaceutical composition comprising the formulation comprising (A) heparin and (B) activated Protein C, and (C) pharmaceutically acceptable carrier (claim 3 and page 3, lines 27-33).
Therefore, the reference of Hirahara anticipates claims 1, 3-5, 8-9, and 15-16.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hirahara (EP 0 326 014 – form PTO-1449), Wildhagen (Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014 Feb 13;123(7):1098-101 – form PTO-1449), Kowalska (Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation. Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):120-6. – 1449), and Patel (Covalent antithrombin-heparin complexes. Thromb Res. 2007;120(2):151-60. – form PTO-892), and evidenced by Yu (Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins—An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic. Front. Mol. Biosci. 7:628551. (2021) – form PTO-892).
Regarding claims 1, 3-5, 8, and 15, Hirahara discloses a formulation comprising (A) heparin, a negatively charged polysaccharide comprising of variably sulphated repeating disaccharide units belonging to glycosaminoglycan (GAG) family, and (B) activated protein C, a serine protease for treating hemostatic disorders, which are driven by histones (Example 1 and claim 1). The formulation of Hirahara reads on a complex because heparin is bound to activated Protein C by van der Waals forces, electrostatic forces, or ionic forces, between the negatively charged heparin and positively charged Lys and Arg residues on Protein C, as evidenced by the instant specification at page 21, lines 18-24 and Yu (see page 4, 1st full paragraph).
Regarding claims 9 and 16, Hirahara discloses a pharmaceutical composition comprising the formulation comprising (A) heparin and (B) activated Protein C, and (C) pharmaceutically acceptable carrier (claim 3 and page 3, lines 27-33).
Hirahara does not disclose a complex comprising an elastase (claims 2 and 13-14), non-anticoagulant heparin (claim 6), chemically O-desulfated heparin (claim 7), treating immunothrombosis related disorder/sepsis (claims 10-11), or Protein C covalently bound to heparin (claim 12)
Regarding claims 2 and 13-14, Wildhagen discloses that neutrophil elastase respond to infection and have antimicrobial properties (page 1098, 1st paragraph). The positively charged Lys and Arg residues of a neutrophil elastase are bound to the negatively charged heparin by van der Waals forces, electrostatic forces, or ionic forces the instant specification at page 21, lines 18-24 and Yu (see page 4, 1st full paragraph).
Regarding claims 6 and 10-11, Wildhagen discloses using a non-anticoagulant heparin in treating sepsis, an immunothrombosis related disorder, without risk of bleeding (abstract)
Regarding claim 7, Kowalska discloses that desulfated heparin (ODSH) increases activated Protein C levels while not causing a bleeding state and using ODSH as a therapeutic (Figure 3 and page 124 “Significance”).
Regarding 12, Patel discloses covalent conjugation of a protein and heparin to improve heparin efficacy and safety. Patel discloses that the rationale for the complex stems from several benefits predicted for covalent linkage, such as when heparin is irreversibly bound to AT, heparin's catalytic role would be specifically directed to its intended target (page 153, 1st paragraph).
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to modify the complex of Hirahara by (1) using a non-coagulant heparin, (2) adding a neutrophil elastase to the complex, (3) covalently bind heparin and activated Protein C, and (4) use the complex to treat sepsis. One having ordinary skill in the art would have been motivated use a non-coagulant heparin or ODSH to treat sepsis without the risk of bleeding. One having ordinary skill in the art would have been motivated to add a neutrophil elastase in treating sepsis because neutrophil elastases respond to infection and have antimicrobial properties. One having ordinary skill in the art would have been motivated covalently bind heparin to activated Protein C in order ensure heparin's catalytic role specifically directed to its intended target. One of ordinary skill in the art would have had a reasonable expectation of success since Hirahara discloses a complex comprising heparin and activated Protein C in treating hemostatic disorders, which are driven by histones, Wildhagen discloses that neutrophil elastase respond to infection and have antimicrobial properties (page 1098, 1st paragraph), Wildhagen discloses using a non-anticoagulant heparin in treating sepsis, an immunothrombosis related disorder, without risk of bleeding, Kowalska discloses that desulfated heparin (ODSH) increases activated Protein C levels while not causing a bleeding state and using ODSH as a therapeutic, and Patent teaches that covalent conjugation of a protein and heparin to improves heparin efficacy and safety and specifically direct heparin to its intended target.
Therefore, the above references render claims 1-16 prima facie obvious.
Conclusion
Claims 1-16 are pending.
Claims 1-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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/YONG D PAK/Primary Examiner, Art Unit 1652
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