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 2 and 4-17 are pending.
Applicant’s amendment to the claims filed 05/26/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Election
Applicant’s election with traverse of
Group I, claims 2-11 and 13-16, drawn to the technical feature of a kallikrein I or a derivative thereof, wherein the kallikrein I is (a) a primate kallikrein I containing three N-glycosylation sites of native kallikrein I at NMS, NHT and NFS, wherein the asparagine at NFS has no glycosylation, or wherein a proportion of glycosylated asparagine at NFS is less than or equal to 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%, or (b) a recombinant primate kallikrein I containing only two N-glycosylation sites; a composition comprising the glycosylated kallikrein I or it’s derivative; and a pegylated kallikrein I or is derivative, and
Applicant’s election without traverse of
A1) the sequence of the kallikrein I is set forth in SEQ ID NO: 3,
B4) the asparagine (N) at NFS is mutated to glutamine (Q), and
C1) a straight chain PEG succinimidyl propionate with molecular weight of 5 – 10 kDa and the general formula as shown in (1), wherein “n” is an integer from 105-225,
in the reply filed 05/26/2026 is acknowledged. The traversal is on the grounds that the claims as amended (particularly the amendment to claim 2) require features of a recombinant primate KLK1 with only 2 N-glycosylation sites of NMS and NHT, and do not comprise the N-glycosylation site at NFS as a result of mutation, which is not disclosed by US 2013/0323222 A1 (cited on the IDS filed 10/30/2024; herein referred to as Charles). Applicant further contends there is no serious search burden in examining all of the presented claims, and therefore the requirement for restriction should be withdrawn.
Applicant’s arguments are considered and not found convincing.
While Charles does not disclose a KLK1 lacking the NFS motif as pointed out by Applicant, the technical feature comprising the features of claim 2 of “a glycosylated kallikrein I or a derivative thereof, wherein the kallikrein I is a recombinant primate kallikrein I containing only two N-glycosylation sites, wherein the glycosylated kallikrein I comprises the N-glycosylation sites at the NMS amino acid sequence and the NHT amino acid sequence of the native kallikrein I, and wherein the glycosylated kallikrein I does not comprise the N-glycosylation site at the NFS amino acid sequence of the native kallikrein I as a result of mutation” is not a special technical feature as it does not make a contribution over the prior art in view of UniProt Accession No. Q9N1Q1_SAGOE (August 12, 2020, 2 pages; cited on the Form PTO-892 mailed 03/23/2026; herein referred to as UNI1), which discloses a primate kallikrein I polypeptide with intact NMS and NHT glycosylation sites and a disrupted NFS glycosylation site [see Appendix A], as the phrase the kallikrein I is a recombinant primate kallikrein I is not a structural limitation of the glycosylated KLK1 of the shared technical feature.
Regarding search burden, the Office action mailed 03/23/2026 sets forth the Requirement for Restriction under 35 U.S.C. 121 and 372, as the application contains the inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1, wherein search burden is not a criteria considered for lack of unity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 12 and 17 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 with traverse in the reply filed on 05/26/2026.
Claims 5-6 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. Election was made without traverse in the reply filed on 05/26/2026.
Claims 2, 4, 7-11, 13-14 and 16 are being examined on the merits only to the extent they read on the elected subject matter.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/CN2022/132102 filed 11/16/2022, which claims foreign priority to Chinese Application No. 202111353294.2 filed 11/16/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 10/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms NEB, THERMO FISHER SCIENTIFIC, THERMOBODY, EXACTIVE, and WATERS, which are trade names or marks used in commerce, have been noted in this application on pages 15-17, and 28. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claim 9 is objected to for the typo in the phrase “amino acid residues 141-143 of of human kallikrein I” in line 5. In the interest of improving claim form, Applicant should consider an amendment to recite “amino acid residues 141-143 of human kallikrein I”.
Claim 13 is objected to for the phrase “Pegylated kallikrein I, wherein the kallikrein I is modified by polyethylene glycol derivatization of the glycosylated kallikrein I or its derivative of claim 2”. In the interest of improving claim form, Applicant should consider an amendment to recite “A pegylated kallikrein I, wherein the glycosylated kallikrein I or its derivative of claim 2 is modified by polyethylene glycol derivatization”.
Claim 16 is objected to for the phrase “a pegylated kallikrein I of claim 13”. In the interest of improving claim form, Applicant should consider an amendment to recite “the pegylated kallikrein I of claim 13” to replace the word “a “ with “the”.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2, 4, 7-11, 13-14 and 16 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 2 (claims 4, 7-11, 13-14 and 16 dependent therefrom) recites the limitations “the N-glycosylation sites at the NMS amino acid sequence and the NHT amino acid sequence of the native kallikrein I”, and “the N-glycosylation site at the NFS amino acid sequence of the native kallikrein I”. There is insufficient antecedent basis for these limitations in the claim.
Claims 2, 4, 7-8 (claims 9-11, 13-14 and 16 dependent therefrom) are indefinite for the phrase “the amino acid sequence … of the native kallikrein I” in claim 2, and “the amino acid sequence … of the kallikrein I” in claims 4 and 7-8 without a reference sequence for comparison. As there is no reference sequence for comparison, one of ordinary skill in the art would be unable to determine the location of the motifs recited in the claim to identify the claimed polypeptide.
Claims 4, 7-10 and 13 (claims 14 and 16 dependent therefrom) are rejected for the phrase “wherein …the kallikrein I”. As each claim recites “a glycosylated kallikrein I” and each claim depends from claim 2 that recites “a recombinant primate kallikrein I”, it is unclear which kallikrein I is being referenced by the use of the phrase.
Claim 9 is indefinite for the phrase “wherein the asparagine, phenylalanine and serine at the NFS amino acid sequence are amino acid residues 141-143 of human kallikrein I” without a reference sequence for comparison. As there is no reference sequence for comparison, one of ordinary skill in the art would be unable to determine the location of the motif recited in the claim to identify the claimed polypeptide.
Claim 9 is indefinite for the recitation of “wherein the amino acid sequence of native human kallikrein I are shown in Genbank accession numbers AAA59455.1, NP002248.1, AAA36136.1, AAP35917, or AAU12569”, as the phrase “shown in” can be interpreted to suggest the Genbank accession numbers are examples of the native human kallikrein I. In view of this interpretation, the phrase “shown in” is considered to be exemplary claim language, and it is unclear as to whether the listed native human kallikrein I sequences are considered to be limiting (see MPEP 2173.05(d)).
Claim 9 is rejected for the recitation of the term “Genbank”, which is a trademark used to identify the product of a polypeptide amino acid sequence. MPEP 2173.05(u) sets forth that trademarks or trade names used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 USC 112(b).
Claim 14 recites the limitation “the PEG modifier” in line 1. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim Interpretation: The claims are drawn to a glycosylated kallikrein I (KLK1) or a derivative thereof, wherein the KLK1 is a recombinant primate KLK1 containing only two N-glycosylation sites, wherein the glycosylated KLK1 comprises the N-glycosylation sites at the NMS amino acid sequence and the NHT amino acid sequence of the native KLK1, and wherein the glycosylated KLK1 does not comprise the N-glycosylation site at the NFS amino acid sequence of the native KLK1 as a result of mutation. With the exception of the NMS and NHT motifs recited in the claim, the remainder of the amino acid sequence of the glycosylated KLK1 protein is unlimited. Additionally, as the instant specification does not specifically define a “derivative”, the “derivative thereof” recited in the claim is considered to be unlimited both in terms of structure and function. Therefore the claims recite a genus of glycosylated KLK1 polypeptides that are structurally unlimited, and a genus of derivative polypeptides that are both structurally and functionally unlimited. In this case, the genus of polypeptides encompasses species that are considered to be widely variant with respect to both structure and function.
A. Claims 2, 4, 7-11, 13-14 and 16 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
MPEP § 2163.II.A.3.(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.II.A.3.(a).ii) 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.II.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. According to MPEP § 2163, “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."
The claims recite (in relevant part) a genus of glycosylated KLK1 polypeptides or derivatives thereof, wherein the KLK1 is a recombinant primate KLK1 containing only two N-glycosylation sites comprising the NMS and NHT amino acid sequences of the native KLK1, and excluding NFS amino acid sequence of the native KLK1. As stated above, with the exception of the NMS and NHT motifs recited in the claim, the remainder of the amino acid sequence of the genus of glycosylated KLK1 proteins is unlimited. Additionally, the genus of “derivatives thereof” recited in the claim is considered to be structurally and functionally unlimited. In this case, the genus of recited polypeptides encompasses species that are considered to be widely variant with respect to both sequence and function.
The specification discloses the following representative species of the genus of glycosylated KLK1 polypeptides and derivatives thereof:
hKLK1X1 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 3;
hKLK1X2 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 4;
hKLK1X3 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 5; and
hKLK1X4 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 6.
Regarding the level of skill and knowledge in the art of amino acid modification, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with residue substitution is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a substitution of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
In view of the high level of unpredictability in the art of amino acid modification, because the genus of glycosylated KLK1 polypeptides and derivatives thereof is widely variant with respect to both structure and function, and the specification discloses the actual reduction to practice of only four representative species among a widely variant genus, 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 the applicant was not in possession of the recited genus of glycosylated KLK1 polypeptides and derivatives thereof. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
B. Claims 2, 4, 7-11, 13-14 and 16 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a glycosylated KLK1 polypeptide or derivative thereof comprising the amino acid sequence of SEQ ID NO: 3, 4, 5 or 6, does not reasonably provide enablement for all glycosylated KLK1 polypeptides or derivatives thereof as 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 beginning on page 2, “KLK1 is an enzyme with rich glycosylations, and the degree of glycosylation has an important effect on the activity of the enzyme. N-glycosylation is the most concerned glycosylation in glycoprotein drugs [… and] the effect of different glycosylation levels of KLK1 on drug efficacy and safety is still inconclusive. […] Even if the best glycosylated KLK1 for drug production is determined, how to control the glycosylation level of glycoprotein is still an important technical problem in modern pharmaceutical production [… and] current KLK1 product have problems such as poor biological stability, short half-life, need for repeated administration, and certain immunogenicity of recombinant proteins. […] Pegylation is a technology that […] can increase protein solubility, improve protein stability, prolong half-life in vivo, and reduce immunogenicity.” The object of the invention is therefore to provide a KLK1 with controlled glycosylation that can be modified by Pegylation to increase protein solubility, improve protein stability, prolong half-life in vivo, and reduce immunogenicity.
The breadth of the claims: The claims recite (in relevant part) a glycosylated KLK1 or derivative thereof, wherein the KLK1 is a recombinant primate KLK1 containing only two N-glycosylation sites comprising the NMS and NHT amino acid sequences of the native KLK1, and excluding NFS amino acid sequence of the native KLK1. As stated above, with the exception of the NMS and NHT motifs recited in the claim, the remainder of the amino acid sequence of the glycosylated KLK1 is unlimited. Additionally, the “derivative thereof” recited in the claim is considered to be structurally and functionally unlimited.
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 “[I]f 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.”
As noted above, other than the recited NMS and NHT motifs in the glycosylated KLK1, the amino acid sequence of the glycosylated KLK1 is unlimited. Additionally, the amino acid sequence of the recited derivative thereof is unlimited, as is the function.
The reference of Singh (supra) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top).
The unpredictability associated with amino acid modification is exemplified by the reference of Zhang (supra) which discloses that even a mutation that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
As such, one of skill in the art would recognize a high level of unpredictability that all glycosylated KLK1 polypeptides and derivatives thereof as encompassed by the claims would maintain the desired activity/utility.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working examples of the recited glycosylated KLK1 polypeptides and derivatives thereof:
hKLK1X1 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 3;
hKLK1X2 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 4;
hKLK1X3 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 5; and
hKLK1X4 corresponding to a polypeptide with the amino acid sequence of SEQ ID NO: 6.
Other than these working examples, the specification fails to disclose any other glycosylated KLK1 polypeptides and derivative thereof. Also, the specification fails to provide guidance for using those glycosylated KLK1 polypeptides and derivatives thereof that are non-functional or have activity other than the expected serine protease function.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: While methods of modifying the amino acid sequence of a polypeptide were known at the time of the invention, it was not routine in the art to make and determine a use for all glycosylated KLK1 polypeptides and derivatives thereof as recited by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, 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).
C. Claim 9 is rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
The relevant portions of 37 CFR 1.57 are as follows:
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a)
The claim is drawn (in relevant part) to a glycosylated KLK1 or a derivative thereof, wherein the asparagine, phenylalanine and serine at the NFS amino acid sequence are amino acid residues 141-143 of human KLK1, respectively, and wherein the amino acid sequences of native human KLK1 are shown in Genbank accession numbers AAA59455.1. NP002248.1. AAA36136.1, AAP35917, or AAU12569 as recited in claim 9.
Accordingly, claim 9 recites essential subject matter, e.g. the sequence database accession number for a reference sequence limiting the claimed polypeptide, without any corresponding sequence identifiers, which fails to satisfy the written description requirement because the claims attempt to incorporate essential subject matter by reference, which is improper. See MPEP § 608.01(p). The complete sequence within the accession number recited in the claims is needed for one of skill in the art to practice the invention. While database accession numbers are provided, its contents are an improper incorporation by reference, as the sequence within the database is essential to the claimed subject matter. Furthermore, the sequence within the database can change at any time, including after the time of filing the instant application. Any version of the sequence within the database after the time of filing of the instant application cannot support the instant claims. Accordingly, claim 9 fails to satisfy the written description requirement.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 2, 4, 7-9 and 11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Applicant’s attention is directed to the "Guidance for Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products”, released on December 16, 2014.
Claim Interpretation: Claim 2 is drawn to a glycosylated KLK1 or a derivative thereof, wherein the KLK1 is a recombinant primate KLK1 containing only two N-glycosylation sites, wherein the glycosylated KLK1 comprises the N-glycosylation sites at the NMS amino acid sequence and the NHT amino acid sequence of the native KLK1, and wherein the glycosylated KLK1 does not comprise the N-glycosylation site at the NFS amino acid sequence of the native KLK1 as a result of mutation. Regarding “a recombinant primate KLK1”, the limitation can be interpreted as a recombinant KLK1 from a primate, wherein “recombinant” is considered drawn to the process of making the claimed glycosylated KLK1. As such, a “recombinant” primate KLK1 does not structurally limit the claimed glycosylated KLK1, and the structural limitations of the glycosylated KLK1 set forth in the claim consist of the motifs NMS and NHT and exclude the motif NFS. Additionally, the claims do not recite any structural limitations for the “derivative thereof” which is recited in the alternative to the glycosylated KLK1. UniProt Accession No. Q9N1Q1_SAGOE (August 12, 2020, 2 pages; cited on the Form PTO-892 mailed 03/23/2026; herein referred to as UNI1) discloses a KLK1 from tamarin, understood to be a primate, that contains the N-glycosylation sites NMS and NHT, but not NFS [see Appendix A], which corresponds to the structural limitations of the glycosylated KLK1 polypeptide in claim 2. Additionally, the KLK1 of UNI1 is encompassed by the structural limitations of the derivative thereof recited in the claim. Claims 4 and 7-9 further limit the glycosylated KLK1 to have specific mutations in the NFS motif, however, the claims do not require the derivative thereof to comprise an NFS motif. Given a broadest reasonable interpretation, claims 2, 4, and 7-9 are directed to a naturally occurring polypeptide.
Claim 11 is drawn to a composition comprising the glycosylated KLK1 or a derivative thereof of claim 2. As the only required component of the composition of claim 11 is the glycosylated KLK1 or a derivative thereof which is considered to encompass the KLK1 of UNI1, given a broadest reasonable interpretation, the claimed composition is considered to encompass a naturally-occurring product, e.g., the KLK1 of UNI1.
Patent Eligibility Analysis Step 1: The claims are drawn to a composition of matter, which is one of the statutory categories of invention.
Patent Eligibility Analysis Step 2A Prong 1: The claims recite a naturally occurring polypeptide, which is considered to be a law of nature or natural phenomena (a natural product). Accordingly, claims 1, 4, 7-9 and 11 are directed to a judicial exception.
Patent Eligibility Analysis Step 2A Prong 2: There are no additional elements recited in the claims beyond the judicial exception.
Patent Eligibility Analysis Step 2B: The claims only recite the product of nature, without more and do not include any additional elements that could add significantly more to the judicial exception.
As such, the claims do not qualify as eligible subject matter. For these reasons the claim is rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 2, 4, 7-9 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCBI Accession No. XP_007531350.1 (2 pages, 11 April 2016; cited on the attached Form PTO-892; herein NCBI1) and evidentiary reference Goettig et al. (Int J Mol Sci, 2016, 17:1969; cited on the attached Form PTO-892; herein Goettig).
Claim 2 is drawn to a glycosylated kallikrein I or a derivative thereof, wherein the kallikrein I is a recombinant primate kallikrein I containing only two N-glycosylation sites, wherein the glycosylated kallikrein I comprises the N-glycosylation sites at the NMS amino acid sequence and the NHT amino acid sequence of the native kallikrein I, and wherein the glycosylated kallikrein I does not comprise the N-glycosylation site at the NFS amino acid sequence of the native kallikrein I as a result of mutation.
Claim 4 is drawn to the glycosylated kallikrein I or derivative thereof of claim 2, wherein the asparagine (N) at the NFS amino acid sequence of the kallikrein I is mutated to any other amino acid, and wherein 0, 1 or 2 amino acids of the F and S residues at the NFS amino acid sequence are independently mutated to any other amino acid.
Claim 7 is drawn to the glycosylated kallikrein I or derivative thereof of claim 4, wherein the asparagine (N) at the NFS amino acid sequence of the kallikrein I is mutated to a neutral polar amino acid, acidic amino acid, basic amino acid, or aliphatic amino acid.
Claim 8 is drawn to the glycosylated kallikrein I or derivative thereof of claim 7, wherein the asparagine (N) at the NFS amino acid sequence of the kallikrein I is mutated to glutamine (Q).
Claim 9 is drawn to the glycosylated kallikrein I or derivative thereof of claim 2,
(a) wherein the glycosylated kallikrein I is the recombinant primate kallikrein I containing only two N-glycosylation sites, and
(b) wherein the kallikrein I is human kallikrein I,
wherein the asparagine, phenylalanine and serine at the NFS amino acid sequence are amino acid residues 141-143 of human kallikrein I respectively; and wherein the amino acid sequences of native human kallikrein I are shown in Genbank accession numbers AAA59455.1, NP002248.1, AAA36136.1, AAP35917, or AAU12569.
Claim 11 is drawn to a composition comprising the glycosylated kallikrein I or derivative thereof of claim 2.
Regarding claim 2, the phrase “wherein the glycosylated KLK1 does not comprise the N-glycosylation site at the NFS amino acid sequence of the native KLK1 as a result of mutation” is considered a product-by-process limitation, wherein the “result of mutation” is drawn to the method of making the claimed glycosylated KLK1 and does not impart any structural limitations on the claimed polypeptide (see MPEP 2113). Additionally, the limitation of “a derivative thereof” is recited in the alternative to “a glycosylated KLK1”, and the derivative thereof is structurally unlimited.
In view of these interpretations regarding claim 2, NCBI1 discloses a KLK1 from Erinaceus europaeus, which contains NMS and NHT motifs, and lacks an NFS motif [see Appendix B], and therefore the KLK1 of NCBI1 satisfies the structural limitations of the derivative thereof recited in the claim. The KLK1 of NCBI1 is additionally considered to correspond to a glycosylated KLK1 as evidenced by Goettig which discloses glycosylation to be a common natural post-translational modification of proteins [abstract] including serine proteases such as KLK1 [page 3, end, to page 4, para 1].
Regarding claims 4 and 8, the KLK1 of NCBI1 contains a mutation at the NFS motif wherein N is mutated to Q relative to SEQ ID NO: 1, and 1 of the F and S residues are mutated to any other amino acid [see Appendix B], wherein SEQ ID NO: 1 is disclosed by the instant specification to be human KLK 1 [page 14].
Regarding claim 7, the KLK1 of NCBI1 contains a mutation at the NFS motif wherein N is mutated to Q relative to SEQ ID NO: 1 [see Appendix B], wherein Q is considered to correspond to a neutral polar amino acid.
Regarding claim 9, the phrase “the glycosylated KLK1 or derivative thereof” is recited in the alternative, and it is noted that parts (a) and (b) limit the glycosylated KLK1 of claim 2, but do not limit the derivative thereof. As the KLK1 of NCBI1 contains two N-glycosylation sites at the NMS and NHT motifs, lacks an NFS motif due to a mutation at the NFS motif of N to Q relative to SEQ ID NO: 1, and the location of the NFS motif in the KLK1 of NCBI1 corresponds to residues 141-143 of human KLK1 [see Appendix B], the KLK1 of NCBI1 satisfies the structural limitations the derivative thereof recited by the claim.
Regarding claim 11, as NCBI1 discloses a KLK1 from Erinaceus europaeus, it is considered to correspond to an organism comprising cells that produce KLK1. As the composition of claim 11 is only required to comprise the glycosylated KLK1 or derivative thereof of claim 2, given a broadest reasonable interpretation, the organism Erinaceus europaeus disclosed by NCBI1 is encompassed by the limitation of a composition recited in the claim.
For these reasons, NCBI1 anticipates claims 2, 4, 7-9 and 11.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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 13-14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over NCBI1 in view of Fadini et al. (Arterioscler Thromb Vasc Biol, 2020, 40:34; cited on the attached Form PTO-892; herein Fadini) and Guerreiro et al. (AAPS PharmSciTech, 2013, 14:1083; cited on the attached Form PTO-892; herein Guerreiro).
Claim 13 is drawn to a pegylated KLK1, wherein the KLK1 is modified by polyethylene glycol derivatization of the glycosylated KLK1 I or its derivative of claim 2.
Claim 14 is drawn to the pegylated KLK1 of claim 13, wherein the PEG modifier is straight chain PEG succinimidyl propionate with molecular weight of 5 kDa – 10 kDa, and the general formula is as shown in (1), wherein n is an integer from 105 to 225.
Claim 16 is drawn to a composition containing a pegylated KLK1 of claim 13.
The teachings of NCBI1 as applied to claims 2, 4, 7-9 and 11 are discussed above. NCBI1 does not teach a pegylated KLK1 modified by polyethylene glycol derivatization of the glycosylated KLK1 I or its derivative of claim 2.
Fadini relates to treatments of diabetic peripheral artery disease [title] and discusses avenues of angiogenic gene therapy for the treatment of diabetic patients, wherein KLK1 is disclosed to be a therapeutic agent for the treatment of acute ischemic stroke and chronic kidney diseases [p 36, col 1, paras 2-3]. Therefore Fadini establishes KLK1 and its importance as a biopharmaceutical.
Guerreiro relates to preparation of PEGylated Amylin [title], and discusses proteins conjugated with PEG have long been known to be a convenient approach for extending the biological effects of biopharmaceuticals, and that PEGylation by succinimidyl derivatives exhibit enhanced reactivity with primary amine groups such as lysines found in proteins [abstract].
Regarding claims 13-14, Guerreiro teaches the modification of the protein amylin via PEGylation with methoxy polyethylene glycol succinimidyl propionate having average molecular numbers of 5 kDa and a polydispersity of 1.08 [p 1084, Sections “Reagents in col 1 and “Amylin PEGylation” in col 2], wherein the substrate used for PEGylation is shown in Figure 1C which corresponds to structure (1) recited in the claim. While Guerreiro does not disclose the repeat number of glycol units “n” shown in structure (1) of the claims and Figure 1C, the estimated molecular weight of the structure in Figure 1C of Guerreiro where n = 1 is approximately 243, and a 5 kDa MW range for the molecule as taught by Guerreiro corresponds to approximately 108 additional units of glycol, and therefore corresponds to the structure according to (1) recited in the claim where n = 109.
In view of Fadini and Guerreiro, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the KLK1 of NCBI1 with a PEG group, as taught by Guerreiro, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the KLK1 of NCBI1 with a PEG group, because Fadini teaches that KLK1 is a biopharmaceutical used to treat acute ischemic stroke and chronic kidney diseases, and Guerreiro teaches PEG conjugation to protein is known to extend the biological effects of biopharmaceuticals. One of ordinary skill in the art would have had a reasonable expectation of success because NCBI1 and Fadini relate to KLK1, and Fadini and Guerreiro relate to biopharmaceuticals and their applications.
Regarding claim 16, Guerreiro teaches the PEGylation of protein in aqueous solution described on [p 1084, col 2, top paragraph], and purification of resulting bioconjugates to the point of lyophilization [p 1085, col 1, para 1], which is considered to correspond to a composition comprising a PEGylated protein.
Therefore, the invention of claims 13-14 and 16 would have been obvious to one of ordinary skill in the art before the effective filing date.
Examiner Comment
The closest prior art of record to the subject matter of claim 10 is considered to be UniProt Accession No. KLK1_HUMAN (8 pages, 02 Dec 2020; cited on the attached Form PTO-892; herein UNI2), which discloses a human KLK1 that shares 99.4%, 99.4%, 99.4% and 99.3% sequence identity with SEQ ID NOs: 3-6, respectively [see Appendices C, D, E and F]. UNI2 does not teach or suggest the amino acid sequence of SEQ ID NOs: 3, 4, 5 or 6, and therefore the subject matter of “the glycosylated kallikrein I or derivative thereof of claim 2, wherein the amino acid sequence of the kallikrein I is set forth in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6” recited in claim 10 is considered to be free of the prior art of record.
Conclusion
Status of the Application:
Claims 2 and 4-17 are pending.
Claims 5-6, 12 and 15 are withdrawn.
Claims 2, 4, 7-11, 13-14 and 16 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
APPENDIX A
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Alignment of SEQ ID NO: 1 with UniProt Accession No. Q9N1Q1_SAGOE, wherein SEQ ID NO: 1 corresponds to the mature protein of human KLK1 [page 14 of the instead specification], and wherein * denotes the NMS, NHT and NFS motifs.
APPENDIX B
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Alignment of SEQ ID NO: 1 with NCBI Accession No. XP_007531350.1, wherein SEQ ID NO: 1 corresponds to the mature protein of human KLK1 [page 14 of the instead specification], and wherein * denotes the NMS, NHT and NFS motifs.
APPENDIX C
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Alignment of SEQ ID NO: 3 with UniProt Accession No. KLK1_HUMAN.
APPENDIX D
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Alignment of SEQ ID NO: 4 with UniProt Accession No. KLK1_HUMAN.
APPENDIX E
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Alignment of SEQ ID NO: 5 with UniProt Accession No. KLK1_HUMAN.
APPENDIX F
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Alignment of SEQ ID NO: 6 with UniProt Accession No. KLK1_HUMAN.
Prosecution Insights