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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 18, 2024 has been entered.
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 July 18, 2025 is acknowledged. Claims 1-12, 14-17, 19-23, and 26-29 are canceled, and claims 33-34 are newly added. Claims 13, 24, and 30-31 are amended. Currently claims 13, 18, 24-25, and 30-34 are pending and under examination.
The previous objections, rejection under 35 U.S.C. 112(b), and non-statutory double patenting rejections in the Final office action mailed April 24, 2024 are withdrawn due to Applicant’s amendments to the claims and terminal disclaimer filed July 18, 2025.
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 and 30 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. This is a new matter rejection.
Claims 13 and 30 as amended recite “selecting a pentosidine oxidase that oxidatively degrades pentosidine at a 5% or lower activity relative to the activity of the amino acid degrading enzyme against its cognate substrate”, and appears to depart from the claims as originally filed and the specification does not describe a ‘selecting pentosidine oxidase’ step, nor a ‘cognate substrate’. Therefore, these limitations constitute new matter. The claimed method as described in the specification is drawn to degrading a specimen with an amino acid degrading enzyme, then further contacting the specimen with the pentosidine oxidase [1-6]. The claimed method as described in the specification is also drawn to the pentosidine oxidase having 5% or lower relative activity to an amino acid degrading enzyme that degrades an amino acid (the preferred amino acid) [0094-0095].
If Applicant believes that such support is present in the specification and claimed priority documents, Applicant should point, with particularity, to where such support is to be found.
Claims 13, 18, 24-25, and 30-34 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 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 claims as currently written 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 specification does not sufficiently describe an amino-acid degrading enzyme that is not pentosidine oxidase. The specification describes the amino acid degrading enzyme preferentially degrades an amino acid contained in the specimen that is not pentosidine, such as arginine, leucine, methionine, phenylalanine, tryptophan, tyrosine, asparagine, glutamine, and histidine, and is selected from the group consisting of amino acid oxidase, amino acid dehydrogenase, amino acid aminotransferase, amino acid decarboxylase, amino acid ammonia lyase, amino acid oxygenase and amino acid hydrolase, and lists species of these amino acid degrading enzymes in Table 1 (para 5, 7, 14, 92). The specification discloses the amino acid degrading enzyme’s activity against pentosidine is 30% or lower than the activity against the preferred amino acid, and has a 5% or higher activity than the pentosidine oxidase towards its preferred substrate (para 93-94).
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 the claimed method utilizing escapin (SEQ ID NO: 15) and Crotalus adamenteus-derived L-amino acid oxidase (SEQ ID NO: 19) to determine foreign substance elimination test in a pentosidine measurement, wherein 17 different amino acids were added to the mixture based on the amount of amino acids in the blood of 18-year old people (para 164, 165, 167, 168). While the genus encompasses a large number of variants that have the same activity as an amino acid degrading enzyme, in kind and the genus encompasses a large number of variants that have a different structure, the specification does not describe the complete structure of a representative number of species of the large genus of amino acid degrading enzymes, or functional equivalents thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than nucleotide sequence or amino acid sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic of an amino acid degrading enzyme is it’s an enzyme different from the protein having activity that oxidatively degrades pentosidine and is an enzyme that can preferentially degrade an amino acid other than an amino acid of pentosidine, which also takes into account substrate specificity. Further the specification identifies the characteristic of the amino acid degrading enzyme as having 30% or lower activity against pentosidine than the protein that oxidatively degrades pentosidine. Other identifying characteristics of the reaction product produced are those produced through a peroxidase reaction, or detecting a reaction product consumed through the reaction, such as oxygen. Such a broad limitation cannot be an identifying characteristic for the claimed diverse genus of amino acid degrading enzymes and the amino acid it degrades, and reaction product produced, since by Applicant’s definition of a functional equivalent thereof all members of the claimed genus will have that characteristic.
The inventions of claims 18, 24-25, and 31-34 require the use of the inventions of claims 13 and 30, and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of the species of amino acid degrading enzymes, of the claimed broad genus is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
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.
Claims 13, 18, 24-25, and 30-34 are 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.
Claims 13 and 30 recite: said pentosidine oxidase is selected from amongst a group of proteins consisting of: (a) a protein comprising an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4; (b) a protein encoded by a nucleotide sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 6: (c) a protein consisting of an amino acid sequence that has a sequence identity of 90% or higher to SEQ ID NO: 2 or SEQ ID NO: 4: and (d) a protein encoded by a nucleotide sequence that has a sequence identity of 90% or higher identity to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 6;…” Proper Markush grouping requires closed claim language, such as ‘selected from the group consisting of’, whereas ‘selected from amongst a group of proteins’ introduces ambiguity as to the members of the closed group, as well as ‘a protein comprising an amino acid sequence as set forth in…’, therefore, the limitation is indefinite. Applicant may obviate this rejection by deleting ‘amongst a group of proteins’ and use closed language, for example, “said pentosidine oxidase is selected from the group the amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4;”. Claims 18, 24-25, and 31-34 are likewise rejected as being dependent on an indefinite claim.
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 18, 31, and 33-34 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 18 and 31 recite filamentous fungi, which improperly broadens the scope of invention for failing to further limit the claims upon which they depend, because the independent claims require a Sarocladium sp. protein sequence, SEQ ID NO:2 or 4, or any protein sequence with 90% or more identity; or a protein encoded by a Sarocladium sp. nucleotide sequence, SEQ ID NO: 1, 3, 5 or 6, or any nucleotide sequence with 90% or more identity. SEQ ID NO:5-6 are artificial sequences derived from Sarocladium sp. that are codon-optimized for expression in Aspergillus, each obtained by artificial gene synthesis on the basis of the amino acid sequences of SEQ ID NO: 2 and 4, according to the specification [0017], [0211], [0124]. Therefore, claims 18 and 31 do not further limit the claims from which they depend.
Claims 33-34 recite “…wherein the activities of the group of proteins against pentosidine have been assayed.” and depend from claims 13 and 30 respectively. Claims 33 and 34 do not recite any structure or further active step to the method and therefore do not properly further limit the claims from which they depend.
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 July 18, 2025 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 specification teaches selecting an amino acid degrading enzyme that has a 5% or higher enzymatic activity against its cognate substrate compared to the oxidative activity of the selected pentosidine oxidase against pentosidine. Thus, the specification teaches selecting a pentosidine oxidase that has an activity against pentosidine that is at least 5% lower than the activity of the amino acid degrading enzyme against its cognate substrate. This necessarily means that the amino acid degrading enzyme and the pentosidine oxidase are selected based on activity screening assays. Applicant argues routine screening assays could easily be performed by one of ordinary skill to determine a pentosidine oxidase selected from the Markush grouping that is 5% lower than the activity of a given amino acid degrading enzyme, without even having knowledge of the pentosidine oxidase amino acid sequence. Of course, the recited selection step also means that the selected protein exhibits some amount of pentosidine oxidase. Thus, the recited selection step also necessarily excludes the selection of any protein that fails to exhibit any pentosidine oxidase activity.
As described in the 112(a) rejection, the specification does not support a ‘selecting step’ nor a ‘cognate substrate’ in the originally filed claims or specification, therefore considered new matter. Furthermore, 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. 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’. Furthermore, Applicant’s arguments that merely a ‘screening step’ could be employed to determine the selection of a functional pentosidine oxidase from the claimed broad genus is not part of the originally filed claimed method. Lastly, Applicant’s claimed broad genus of ‘an amino acid degrading enzyme that is different from the pentosidine oxidase Markush grouping’ is not adequately supported, as the broad genus of amino acid degrading enzymes could include many types of amino acid degrading enzymes derived from prokaryotes and eukaryotes, other than the ones listed in Table 1 of the specification, which are not demonstrated in the claimed method.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA EDWARDS whose telephone number is (571)270-0938. The examiner can normally be reached M-F 8am-5pm EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657