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 US national phase of PCT/JP2020/031553, filed August 21, 2020, with foreign priority application JP2019-154965, filed August 27, 2019.
Applicant’s amendment filed April 9, 2026 is acknowledged. Claims 1-12, 14-23, 26-29, 31, 33-34 are canceled, and claims 35-37 are newly added. Claims 13 and 30 are amended. Currently, claims 13, 24-25, 30, 32, and 35-37 are pending and under examination.
Claim Objections
New claim 37 is objected to because of convoluted language and typographical errors. Claim 37 may be amended to: A method for measuring pentosidine in a specimen, t
degrading the specimen by contacting with an amino acid degrading enzyme selected from the group consisting of: L-amino oxidase, Glutamate dehydrogenase, Leucine dehydrogenase, Alanine dehydrogenase, Alanine aminotransferase, Aspartate aminotransferase, Glutamate decarboxylase, Aspartate decarboxylase, Arginine decarboxylase, Lysine decarboxylase, Histidine decarboxylase, Phenylalanine decarboxylase, Tyrosine decarboxylase, Tryptophan decarboxylase, Histidine ammonia lyase, Phenylalanine ammonia lyase, Tyrosine amino lyase, Tryptophan dioxygenase, Asparagine hydroxylase, Arginase, Glutaminase, and Asparaginase;
producing a recombinant protein derived from a pentosidine oxidase of a Sarocladium sp.;
assaying pentosidine oxidase activity of the recombinant protein at room temperature
sequencing the recombinant protein;
contacting the degraded specimen with the recombinant protein, wherein recombinant protein has 90-100% sequence identity to SEQ ID NO: 2 or SEQ ID NO: 4;
detecting a change in an amount of oxygen, hydrogen peroxide, or ammonia resulting thereby.
Appropriate correction is required.
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 13, 24-25, 30, 32, and 37 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus."
The specification does not sufficiently describe a genus of pentosidine oxidase species derived from Sarocladium sp. that has 90% identity to amino acid SEQ ID NO’s 2 or 4, or to a nucleic acid encoded by SEQ ID NO’s 1, 3, 5, or 6, and that oxidatively degrades pentosidine at a 5% or lower activity relative to the activity of the amino acid degrading enzyme against its cognate substrate. In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification merely gives working examples of putative pentosidine oxidase genes encoded by SEQ ID NO’s: 1 and 3 that encode amino acid sequences SEQ ID NO’s: 2 and 4 (penox1 and penox2), both derived from Sarocladium sp. (para 122, 211). The specification also discloses SEQ ID NO’s: 5 and 6 are codon optimized for expression in Aspergillus (para 124). Both penox1 and penox2 exhibited pentosidine oxidizing activity, though further experiments were conducted with only penox2 (para 141). Further, the specification discloses that pentosidine oxidase is a novel enzyme, suggesting that methods of identifying other proteins that oxidatively degrade pentosidine is unpredictable (para 6-7). The current specification describes a single embodiment of the enzymes isolated from a filamentous fungus of the genus Sarocladium (para 110 (Example 1)). The current specification indicates that the amino acid sequences of the pentosidine oxidase 1 protein (PenOX1) and the pentosidine oxidase 2 protein (PenOX2) are set forth in SEQ ID NOs: 2 and 4, respectively. However, a sequence search of SEQ ID NOs: 2 and 4 yielded results with less than 76% sequence homology, indicating that these sequences were not known in the art at the time of invention.
The claims require a polypeptide having the aforementioned activity with at least 90% sequence identity to the aforementioned SEQ ID’s. However, the specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus as to establish a structure-function relationship with respect to the activity, such as active site residues required for such activity. For example, SEQ ID 2: is 689 amino acids long. A protein sharing only 90% identity relative to SEQ ID: 2 could have anywhere from 1 to 68 substitutions, deletions or additions in any combination along any length of SEQ ID: 2. Thus, an enormous genus (2067 = 1.5 x 1087) comprising literally more than trillions of sequences is encompassed by the tremendously broad scope of the claims.
However, while the claim is drawn to a genus that comprises literally trillions of sequences, the specification has only adequately described and successfully reduced to practice the full-length of SEQ ID NO’s 1-6. Further the specification has only successfully reduced to practice SEQ ID NO: 4 in the method claims. At best, the specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Thus, one of skill in the art would readily appreciate that relying on a non-patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
Moreover, Friedberg (Brief. Bioinformatics (2006) 7: 225-242, previously cited in PTO-892 mailed 11/6/2024) teaches that homology-based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub-regions is critical to functional annotation, and that often addition, deletion, or re-shuffling of domains can lead to errors in annotation (page 227, second column, page 228, first paragraph). Furthermore, Friedberg teaches that sequence-based tools are just not sensitive enough to identify functional protein similarity as databases get larger, and diversity of sequences gets larger (page 228, first full paragraph).
Thorton et al. (Nature structural biology, structural genomics supplement, November 2000, pgs. 991-994, previously cited in PTO-892 mailed 11/6/2024) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton et al. further describe examples of little correlation between specific enzyme function and overall protein structure (see page 992, right column, at lines 2-10).
Thus, when taken with the teachings of Friedberg and Thorton, one of skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function.
In the absence of a representative number of examples and any art-recognized structure-function relationship, the specification must at least describe the structural features that are required for the claimed function. However, as discussed above, the specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to the aforementioned proteins’ activity or expression and mutation/sequence modification. Instead, Applicant merely offers a statement that any polypeptide that has the aforementioned protein’s activity will work.
Accordingly, the instant claims are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
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 37 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.
Claim 37 recites, “A method for measuring pentosidine in a specimen, the measurement method comprising the steps of:… sequencing the protein;…”. It is unclear of the interrelationship between ‘sequencing the protein’ with the other recited method steps, and how sequencing the protein is a “method for measuring pentosidine in a specimen”, thus is indefinite. To obviate this rejection, the Examiner recommends deleting this step, and adding a wherein clause, such as “wherein the protein derived from Sarocladium sp. has 90-100% sequence identity to SEQ ID NO: 2 or 4;”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 25 and 32 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 25 and 32 recite genera of amino acid degrading enzymes, and depend upon claims 13 and 30, which recite species of amino acid degrading enzymes, thus the limitation of claim 25 or claim 32 improperly broadens the scope of the claim invention and fails to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant's arguments filed April 9, 2026 have been fully considered but they are not persuasive.
Regarding the 112(a) written description rejection, Applicant argues the specification provides sufficient written support for the claims, because the amended claims define the pentosidine oxidase as a protein derived from a Sarocladium sp. that (a) has been assayed as having pentosidine oxidase activity at room temperature and (b) is selected from exact sequences (SEQ ID NOs: 2 and 4 or encoding nucleic acids SEQ ID NOs: 1, 3, 5, and 6) or those having 90% or higher sequence identity thereto. This is not an unbounded functional genus but a structurally anchored, functionally validated, and source-limited genus. That is, the instant claims are not compound or antibody composition claims whereby the structural features of the compound or antibody itself must be specified in the claims. Instead, the instant method claims require that the protein being used in the method as the 'PenOX enzyme' has "been assayed as having pentosidine oxidase activity at room temperature". Applicant argues the ’trillions of sequences’ calculation is misplaced, and he 90% identity threshold and the pentosidine oxidase activity assays of the low-homology proteins of Example 10 confirm a strong structure-function correlation, whereby one skilled in the art can reliably assume based on the detailed experiments in the specification that proteins having at least 90% sequence identity to SEQ ID NOs: 2 or 4 will exhibit pentosidine oxidase activity. Even if the "90% or higher" sequence identity limitations happen to include a small number of proteins that completely lack pentosidine oxidase activity, the U.S. Court of Appeals for the Federal Circuit has long recognized the pragmatic doctrine the mere inclusion of a small number of inoperative species within the scope of a claimed genus does not, by itself, defeat compliance with the written description requirement of 35 U.S.C. § 112(a). This doctrine reflects the reality that scientific and technological progress rarely yields perfectly uniform results across every possible embodiment; inventors are not required to describe or reduce to practice every conceivable variant or to guarantee operability of every member of a broadly claimed genus. See, e.g., Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)
As described in the 112(a) rejection, there are no defined structural features of the protein or nucleic acid that are required for the functional activity specified in the claims, such as any active site residues that are required for the claimed enzymes. The Specification describes the putative pentosidine oxidase genes (SEQ ID NO: 1 and SEQ ID NO: 3) and amino acid sequences thereof (SEQ ID NO: 2 and SEQ ID NO: 4) were identified on the basis of the sequence information on the whole genome of Sarocladium sp and working examples [0211], absent of any identified structural features or active sites of the claimed functional protein. As mentioned in the 112(a) rejection, the claimed broad genus of 90% identity includes more than trillions of variants in the enormous scope of the claims, and the newly added limitation of ‘derived from Sarocladium sp.’ is broad in scope, because it does not require resemblance to the original or source at all, unless the specification defines the term and provides the limits to the variation from any single structure. A definition by function does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus.". Applicant’s disclosure that SEQ ID NO’s 2 and 4 only share 38.2% sequence identity further underlines the variability in structural requirements for the claimed function, which one of ordinary skill in the art would have trouble ‘visualizing or identifying members of the genus’. Therefore, the 112(a) written description rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657
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