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 .
Election/Restrictions
Applicant’s election without traverse of Group III (i.e., claims 14-16 drawn to a method for treatment of a disease caused by a viral infection with a virus, in the infection of which serine proteinases are involved, and slowing down the spread of infection of the virus by administering a polypeptide having an amino acid sequence selected from at least 70% identity to any one of domains 1-14 of LEKTI, SPINK6 or SPINK9 polypeptide) in the reply filed on December 1, 2025, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., LEKTI domain 2 (i.e., SEQ ID NO: 2) as a single and specific polypeptide); and Species B (i.e., influenza as a single and specific virus) in the telephonic interview on February 26, 2026, is acknowledged.
Please note that after further consideration, Species A is hereby removed.
Status of Claims
Claims 1-16 were originally filed on September 29, 2022.
The amendment received on September 29 2022, amended claims 3-13 and 16; and added new claims 17-20.
Claims 1-20 are currently pending and claims 14-16 are under consideration as Claims 1-13 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 December 1, 2025.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/058150 filed March 29, 2021, and claims priority under 119(a)-(d) to European Application Nos. 20184401.6 filed on July 7, 2020, and 20167370.4 filed on March 31, 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for European Application Nos. 20184401.6 and 20167370.4, which papers have been placed of record in the file. Please note that the European applications are in a foreign language and therefore cannot be verified.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 29, 2022 is being considered by the examiner.
Claim/Sequence Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 14, please note that the Examiner is interpreting the scope as open-ended requiring at least 70% identity to any one of a LEKTI domain 1-14 (i.e., SPINK5), SPINK6, or SPINK9 polypeptides with any N- and/or C-terminal additions. As further discussed below in the 112(a) rejection, the LEKTI domain/SPINK5/9 polypeptide is not limited. However, for prior art purposes, Applicants election of SEQ ID NO: 2 encompasses up to 25 amino acid modifications such as deletions, substitutions and/or insertions. Furthermore, it is noted that given the transitional phrase “having”, the polypeptide requires at least 70% identity to SEQ ID NO: 2, but since it encompasses any N- and/or C-terminal additions, it also encompasses the full length LEKTI protein containing all domains.
Additionally, it is noted that LEKTI stands for lympho-epithelial kazal-type-related inhibitor or serine protease inhibitor kazal-type 5 (SPINK5) (See instant pg. 1, 4th paragraph). It is noted that the word “Kazal-type” in LEKTI is a known term in the art. Bitoun et al. identified SPINK5 (serine protease inhibitor Kazal-type 5) as the defective gene in Netherton syndrome (NS) where a total of 34 SPINK5 mutations have been reported in patients (See Bitoun et al., Human Molec. Genet. 12:2417-2430 (2003) at pg. 2418, col. 1, 2nd paragraph). Bitoun et al. also teaches that SPINK5 encodes LEKTI (lympho-epithelial Kazal-type related inhibitor), which is a predicted serine protease inhibitor (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). The protein consists of 1064 amino acids organized into 15 potential inhibitory Kazal-type domains (D1-D15) (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). Only D2 and D15 perfectly match the typical Kazal motif [C-(X)n-C-(X)7-C-(X)10-C-(X)2/3-C-(X)m-C], whereas the other domains exhibit a Kazal-type-derived four cysteine residue pattern (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). Thus, an ordinary skilled artisan would be well aware of what is referred to as a “Kazal-type”.
Furthermore, it is noted that the scope of claim 14 does not require treatment of a subject/patient who suffers from a disease caused by a viral infection and who is in need of slowing down the spread of infection. Nor does claim 14 require that the polypeptide is administered to such a subject/patient. Thus, the scope of claim 14 encompasses any treatment including in vitro and in vivo administration.
For claim 16, please note that the Examiner is interpreting the scope as open-ended requiring at least 80% identity to any one of a LEKTI domain 1-14 (i.e., SPINK5), SPINK6, or SPINK9 polypeptides with any N- and/or C-terminal additions. As further discussed below in the 112(a) rejection, the LEKTI domain is not limited. However, for prior art purposes, Applicants election of SEQ ID NO: 2 encompasses up to 15 amino acid modifications such as deletions, substitutions and/or insertions.
Drawings
Figures 1-3 are objected to because each figure depicts amino acid sequences without a sequence identifier. Please note that the SEQ ID NOs: need to be present in either the figure or the Brief Description of the Drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings; in particular, Figures 1 and 3, are objected to because of the following reason:
The drawings have a line quality that is too light to be reproduced (weight of all lines and letters must be heavy enough to permit adequate reproduction) or text that is illegible (reference characters, sheet numbers, and view numbers must be plain and legible) see 37 CFR 1.84(l) and (p)(1)); See Figure(s) 1 and 3.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Please see pg. 2, 2nd paragraph and pg. 3, 7th paragraph. 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 Objections
Claim 14 is objected to because of the following informalities: claim 14 recites, “SPINK9-polypeptide.” It is respectfully requested that claim 14 recites, “SPINK9 polypeptide.” Such amendment would render the claim language grammatically correct. Appropriate correction is required.
Claims 14 and 16 are objected to because of the following informalities: claim 14 recites, “LEKTI, SPINK6 or SPINK9….” 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). The Examiner respectfully requests that Applicant uses lympho-epithelial kazal-type-related inhibitor (LEKTI), serine protease inhibitor kazal-type 6 (SPINK6), or serine protease inhibitor kazal-type 9 (SPINK9)…” for the first recitation, thereafter LEKTI, SPINK6, and SPINK9 may be utilized. Appropriate correction is required.
Improper Markush Grouping
Claims 14-15 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of polypeptides in claim 14 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons. Claim 14 recites a Markush grouping of polypeptides by reciting that the administered polypeptide has an amino acid sequence selected from at least 70% sequence identity to any one of domains 1 to 14 of LEKTI, SPINK6 or SPINK9 polypeptide. By encompassing at least 70% identity, the polypeptide amino acid sequences of the Markush group does not share a substantial structural feature and a common use that flows from the substantial structural feature. As further articulated in the 112(a), written description, rejection below, there is no required core structure or sequence shared among the species of the claimed genus that is necessary for the polypeptide amino acid sequence to exhibit the common use of treating a disease caused by a viral infection and slowing down the spread of the viral infection. For example, LEKTI domain 2 (i.e., SEQ ID NO: 2) is 76 total amino acids. As such, at least 70% identity to SEQ ID NO: 2 encompasses up to 25 amino acid modifications including deletions, substitutions, and/or insertions. Moreover, the LEKTI domains and SPINK6 and 9 polypeptide sequences that are to represent the base amino acid sequence to determine sequence identity is not limited thereby encompassing any LEKTI domains, SPINK6/9 polypeptides derived from any source. Thus, the alternatives encompassed by the claimed Markush group do not share both a substantial structural feature and common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. A suggested amendment for claim 14 can be “….a polypeptide having an amino acid sequence comprising at least 70% identity to one of human LEKTI domains 1-14, human SPINK6 or human SPINK9 polypeptides.” An alternative suggested amendment can be “….a polypeptide having an amino acid sequence comprising at least 70% identity to an amino acid sequence selected from SEQ ID NOs: 1-35.”
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 14-16 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.
Independent claim 14 includes a “polypeptide having an amino acid sequence that has at least 70% identity to any one of LEKTI domains 1-14, SPINK6 or SPINK9 polypeptides”. Similarly, dependent claim 16 includes a “polypeptide having an amino acid sequence that has at least 80% identity to any one of LEKTI domains 1-14, SPINK6 or SPINK9 polypeptides”. It is noted that the LEKTI domains 1-14, SPINK6 or SPINK9 polypeptides are not limited thereby encompassing any amino acid sequence that constitutes the full length domain or SPINK polypeptide from any mammalian source. For example, SEQ ID NO: 2 represents the human LEKTI domain 2 whereas GenBank Accession No. XP_008253430.2 (GenBank Accession No. XP_008253430.2, 2 pages (2024)) represents the rabbit LEKTI domain 2 amino acid sequence at residues 80-155. Since there is about 71% identity between the human and rabbit LEKTI domain 2 amino acid sequences, the scope of the claimed amino acid sequence would encompass any sequence at least 70% identical to either the human or rabbit LEKTI domain 2 sequences. As such, the scope of the administered polypeptide amino acid sequence encompasses an enormous array of sequences that do not require a shared core structure or sequence/residues. Furthermore, the administered polypeptide must exhibit the function of treating a disease caused by a viral infection and slowing down the spread of the viral infection. Thus, given the breadth of the claimed genus, there is no core structure or sequence/residues shared among the claimed species that would be necessary for the species to exhibit the claimed function of treating a disease caused by a viral infection and slowing down the spread of the viral infection.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, WO 03/070953 A1 teaches RLD 8564 to treat viral infections such as HIV (See WO 03/070953 A1 published on August 28, 2003 at English language translation, pg. 1, 1st and 8th paragraph) (published WIPO publication cited in the IDS received on 9/29/22). ‘953 teaches that the RLD 8564 is the 15th domain of the serine proteinase inhibitor LEKTI where the first two residues at the N-terminus do not correspond to the sequence from the LEKTI protein and are of the origin of the cloning and cleavage of the starting peptide (See ‘953 English language translation, pg. 1, 3rd paragraph). ‘953 also teaches fragments, analogs and/or derivatives of RLD 8564 such as N-terminally shortened by 1-3 amino acids, C-terminally shortened by 1-3 amino acids in which a maximum of 10% of the amino acids have been replaced or deleted, or a maximum of 5 further amino acids have been inserted, glycosylation, amidation, acetylation, sulfation, and phosphorylation (See ‘953 English language translation, pg. 1, 4th paragraph). However, ‘953 only demonstrates that RLD 8564 functions as an inhibitor to treat HIV (See ‘953 English language translation, pg. 1, 8th paragraph), and does not teach any specific species of RLD 8564 fragments or analogs. Furthermore, it is noted that RLD 8564 is not at least 70% identical to any of LEKTI domains 1-14, SPINK6, or SPINK9 polypeptides. Thus, the claims are directed to polypeptide amino acid sequences with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches polypeptide amino acid sequences of SEQ ID NOs: 1-35 where SEQ ID NO: 1 corresponds to LEKTI domain 1, SEQ ID NO: 2 corresponds to LEKTI domain 2, SEQ ID NOs: 3-4 corresponds to LEKTI domain 3, SEQ ID NOs: 5-8 correspond to LEKTI domain 4, SEQ ID NOs: 9-10 correspond to LEKTI domain 5, SEQ ID NOs: 11-18 correspond to LEKTI domain 6, SEQ ID NO: 19 corresponds to LEKTI domain 7, SEQ ID NOs: 20-21 correspond to LEKTI domain 8, SEQ ID NOs: 22-23 correspond to LEKTI domain 9, SEQ ID NOs 24-25 correspond to LEKTI domain 10, SEQ ID NOs: 26-29 correspond to LEKTI domain 11, SEQ ID NOs: 30-31 correspond to LEKTI domain 12, SEQ ID NOs: 32-33 correspond to LEKTI domain 13, SEQ ID NOs: 34-35 correspond to LEKTI domain 14, and SEQ ID NO: 36 corresponds to LEKTI domain 15 (See instant Figure 1). Moreover, the specification teaches SEQ ID NOs: 37-39 where SEQ ID NO: 37 correspond to the SPINK6 amino acid sequence, SEQ ID NO: 38 corresponds to the SPINK6 signal peptide, and SEQ ID NO: 39 corresponds to the mature SPINK6 amino acid sequence (See instant Figure 3). The specification also teaches SEQ ID NOs: 40-42 where SEQ ID NO: 40 corresponds to the SPINK9 amino acid sequence, SEQ ID NO: 41 corresponds to the SPINK9 signal peptide, and SEQ ID NO: 42 corresponds to the mature SPINK9 amino acid sequence (See instant Figure 3). Although the specification teaches variant LEKTI domains 3-6 and 8-14, these species do not constitute a representative number of species of the claimed genus given the breadth of the genus. For example, the two sequences that correspond to LEKTI domain 8 (i.e., SEQ ID NOs: 20-21) are 97% identical. As discussed supra, the claimed polypeptides encompass sequences with up to 25 amino acid differences to the LEKTI domain 2 polypeptide and up to 21 amino acid differences to the LEKTI domain 6 polypeptides. As such, the disclosed LEKTI amino acid sequences constitute a small portion of the scope of the claimed genus. Therefore, the specification does not provide a representative number of species that an ordinary skilled artisan can extend to the scope of the claimed genus. Thus, the specification is not sufficient for the skilled artisan to envisage which polypeptide amino acid sequences are at least 70% or 80% identical to one of a LEKTI domain 1-14, SPINK6, or SPINK9 polypeptides and will preserve the claimed function.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 14-16 do not meet the written description requirement.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding claim 15, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Please note that the Examiner is interpreting the scope of claim 15 such that the scope of the claim is limited to an influenza virus or a coronavirus in order to advance prosecution.
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding claim 16, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Please note that the Examiner is interpreting the scope of claim 16 such that the scope of the claim is directed to wherein the polypeptide has at least 80% identity to one of domains 1-14 of LEKTI, SPINK6, or SPINK9 polypeptides, or wherein the polypeptide has at least 80% identity to one an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-21, 23-24, and 26 in order to advance prosecution.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kido et al., Biochimie 166:203-213 (2019) in view of Jayakumar et al., Prot. Expr. Purification 35:93-101 (2004), alone or as evidenced by Margert et al., Intl. J. Biochem. Cell Biol. 34:573-576 (2002).
For claims 14-16, Kido et al. teaches that influenza A virus (IAV) is the most common infective pathogen in human causing significant morbidity and mortality in infants and the elderly every year (See Kido, pg. 203, col. 1, last paragraph to col. 2, 1st paragraph). Kido et al. teaches that during the IAV infection, proteolytic conversion of hemagglutinin precursor (HA0), the viral envelope fusion glycoprotein, into HA1 and HA2 subunits by the host cellular trypsin-type serine proteases is a pre-requisite for viral membrane fusion activity because HA-processing proteas(s) is not encoded in their genomes (See Kido, pg. 204, col. 1, 2nd paragraph). Therefore, cellular trypsin-type serine HA-processing proteases are the main determinants of IAV entry and transmission, and determine viral infectious tropism of organs and species (See Kido, pg. 204, col. 1, 2nd paragraph). Furthermore, once the initial IAV infection ensues in the respiratory tract, cellular ectopic trypsin, one of the HA processing serine proteases, together with pro-matrix metalloproteinase-9 (MMP-9), are successively induced through the induction of pro-inflammatory cytokines as a secondary reaction in various organs and vascular endothelial cells (See Kido, pg. 204, col. 1, 2nd paragraph). The induced trypsin potentiates not only viral multiplication in various organs but also causes cellular dysfunction and fluid imbalance through proteinase-activated receptor-2 (PAR-2) pathway (See Kido, pg. 204, col. 1, 2nd paragraph Fig. 4). The close interaction among IAV infection, cytokines and cellular ectopic trypsin to induce influenza pathogenicity is coined the “influenza virus cytokine trypsin” cycle (See Kido, pg. 204, col. 1, 2nd paragraph). Kido et al. identifies several secreted and membrane-anchored trypsin-type serine HA processing proteases for human IAV including pancreatic trypsin, ectopic trypsin, plasma kallikrein, kallikrein 5, and kallikrein 12 (See Kido, pg. 204, col. 2, 1st paragraph; Table 1). Plus, Kido et al. found that trypsin efficiently activated the infectivity of all IAV strains tested (See Kido, pg. 204, col. 2, 3rd paragraph; Fig. 1).
Furthermore, Kido et al. teaches that under physiological conditions, the host cellular trypsin-type serine HA-processing proteases are regulated by endogenous serine protease inhibitors, but the levels of these natural inhibitory compounds are lower than those of trypsin-type serine HA-processing proteases under conventional airway conditions (See Kido, pg. 208, col. 2, last paragraph). Thus, there are a number of known antiviral agents that selectively reduce the replication of influenza A and B viruses (See Kido, pg. 208, col. 2, last paragraph). However, resistant influenza viral strains are being reported (See Kido, pg. 208, col. 2, last paragraph to pg. 209, col. 1, 1st paragraph). To overcome this issue, Kido et al. sought alternative antiviral drugs such as HA-processing protease inhibitors (See Kido, pg. 209, col. 1, 1st paragraph). In particular, Kido et al. teaches that new drugs with new modes of action such as disruption of the link between the “influenza virus-cytokine-trypsin cycle” are desirable (See Kido, pg. 209, col. 1, last paragraph). Kido et al. also teaches that treatment of influenza in particular, severe IAV that can lead to multiple organ failure, can be accomplished by providing an inhibitor of a trypsin-type serine HA-processing protease such as trypsin, which would then preclude proteolytic cleavage of HA0, and subsequent, IAV entry and transmission thereby disrupting the “influenza virus-cytokine-trypsin cycle”. Such inhibition would necessarily slow down the spread of IAV. Thus, the teachings of Kido et al. constitute the administration of an inhibitor of a trypsin-type serine HA-processing protease such as trypsin in order to treat an influenza infection in which serine proteases are involved by inhibiting proteolytic cleavage of HA0, and subsequent, IAV entry and transmission and disruption of the “influenza virus-cytokine-trypsin cycle”. Therefore, the teachings of Kido et al. satisfy the claim limitations with respect to treatment of a disease caused by a viral infection with a virus, in the infection of which serine proteinases are involved and slowing down the spread of infection of the virus as recited in instant claim 14 where the virus is influenza as recited in instant claim 15.
However, Kido et al. does not expressly teach that the trypsin-type serine HA-processing protease is a polypeptide having an amino acid sequence that has at least 70% identity to LEKTI domain 6 or a fragment comprising LEKTI domains 6-9.
Jayakumar et al. teaches that LEKTI is an efficient inhibitor of multiple serine proteases including plasmin, subtilisin A, cathepsin G, elastase and trypsin (See Jayakumar, abstract). More specifically, Jayakumar et al. found that purified recombinant LEKTI domains 6-9 inhibited trypsin and subtilisin A via a non-competitive mechanism whereas LEKTI domain 6 only inhibited trypsin via a competitive mechanism (See Jayakumar, abstract; pg. 94, col. 1, last paragraph; pg. 97, col. 2, last paragraph; pg. 99, col. 1, last paragraph to col. 2, 1st paragraph; Table 2). Jayakumar et al. determined the inhibitory activity of the LEKTI fragments by utilizing the baculovirus expression vector systems (BEVS), which have become widely used in studies on eukaryotic proteins (See Jayakumar, pg. 95, col. 2, 4th paragraph). As such, Jayakumar et al. administered recombinant baculovirus encoding LEKTI domains 6-9 or LEKTI domain 6 to Sf9 cells (See Jayakumar, pg. 95, col. 2, last paragraph). The rLEKTI6-9 contains LEKTI domain 6 (residues 356-425), LEKTI domain 7 (residues 426-489), LEKTI domain 8 (residues 490-560), and LEKTI partial domain 9 (residues 561-598) (See Jayakumar, pg. 96, col. 1, 1st paragraph). As evidenced by Marget et al., residues 356-425 (i.e., domain 6) are 97% identical to instant SEQ ID NO: 11 (note: two amino acid differences at positions 13 and 65 of instant SEQ ID NO: 11). Thus, the rLEKTI6-9 fragment constitutes a polypeptide having an amino acid sequence that has at least 70% identity (i.e., 100% identity) to any one of domains 6, 7, or 8 of LEKTI, and the rLEKTI6 constitutes a polypeptide having an amino acid sequence that has at least 70% identity (i.e., 100% identity) to domain 6 of LEKTI as recited in instant claim 14, and a polypeptide that has at least 80% identity to domain 6 of LEKTI or instant SEQ ID NO: 11 as recited in instant claim 16. Although Jayakumar et al. teaches that the digestive enzyme trypsin is unlikely to be a physiological target proteinase of LEKTI6-9, because subtilisin A is also a target of rLEKTI6-9, LEKTI may well play a role in antimicrobial protection (See Jayakumar, pg. 97, col. 2, last paragraph). Therefore, Jayakumar et al. demonstrates that when either recombinant LEKTI domains 6-9 or recombinant LEKTI domain 6 is administered to cells, they both exhibit trypsin inhibition and the rLEKTI6-9 fragment also exhibits subtilisin A inhibition thereby suggestive of a role in antimicrobial protection. Thus, when the teachings of Jayakumar et al. are combined with those of Kido et al., an ordinary skilled artisan would be motivated with a reasonable expectation of success to substitute either rLEKTI6-9 or rLEKTI6 as an inhibitor of a trypsin-type serine HA-processing protease such as trypsin, which would then preclude proteolytic cleavage of HA0, and subsequent, IAV entry and transmission thereby disrupting the “influenza virus-cytokine-trypsin cycle” and slowing the spread of the IAV.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Kido et al. and administer either rLEKTI6-9 or rLEKTI6 as an inhibitor of a trypsin-type serine HA-processing protease such as trypsin in vitro or in vivo in order to treat an IAV infection by inhibiting proteolytic cleavage of HA0, and subsequent, IAV entry and transmission thereby disrupting the “influenza virus-cytokine-trypsin cycle” and slowing the spread of the IAV. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because rLEKTI6-9 and rLEKTI6 were known to inhibit trypsin, and rLEKTI6-9 was known to inhibit trypsin and subtilisin A thereby suggestive of a role in antimicrobial protection as taught by Jayakumar et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that an inhibitor of a trypsin-type serine HA-processing protease such as trypsin of Kido et al. would treat an IAV infection by inhibiting proteolytic cleavage of HA0, and subsequent, IAV entry and transmission thereby disrupting the “influenza virus-cytokine-trypsin cycle” and slowing the spread of the IAV, and therefore, substituting rLEKTI6-9 or rLEKTI6 as the inhibitor of a trypsin-type serine HA-processing protease such as trypsin would support IAV treatment by inhibiting proteolytic cleavage of HA0, and subsequent, IAV entry and transmission thereby disrupting the “influenza virus-cytokine-trypsin cycle” and slowing the spread of the IAV by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654