DETAILED ACTION
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 .
Priority
Acknowledgments are made that this application claims the priority to the following:
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Information Disclosure Statement
Filed information disclosure statements (IDS) comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Response to Restriction
Applicant's response to restriction requirement and election of group II corresponding to claims 30-32 and 71-87, without traverse, in the reply filed on 02/06/2026 is acknowledged.
The examiner also acknowledges applicants response to election of species and providing a single species for the claimed variables. It appears that applicants elected species are free of art. Following an extensive search and examination, the originally elected species has been deemed free of the prior art. Per MPEP § 803.02, “If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended”. Accordingly, the search has been extended to the full scope of claimed method. The broadest genus has been rejected under 35 USC 112(a) as explained below.
The claims 30-32 and 71-87 are examined on merits in this office action.
Claim Rejections - 35 USC § 112 – Written Description
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 30-32 and 71-87 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 for the claimed method. 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.
The rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:
Independent claim 30 is drawn to a method for modulating a level of a biomarker by administering to a subject a therapeutically effective amount of an isolated, synthetic, or recombinant polypeptide comprising an amino acid sequence of LKGI (SEQ ID NO.5), wherein the polypeptide comprises no more than 100 amino acids.
The term “comprising” is an open language and does not exclude other components in the recombinant polypeptide.
Polypeptide is an active agent for the claimed method and all it requires is recited 4 amino acids and remaining can be any amino acid or all possible amino acids in all possible combinations. In other words, if polypeptide is 100 amino acids in length, claimed 4 amino acids can control the property of polypeptide, regardless of the properties of remaining 96 amino acids.
Recited ‘modulating a level of a biomarker’ means levels of biomarker can go up or down, depends on specific condition, in all possible biomarkers and in all possible cells.
Administration can be any known mode of administration to all possible subjects.
Dosage amount of polypeptide is very generic.
Dependent claims 31-32, 71-83 define biomarkers, level of modulation and their associated inflammatory condition or disorder, wherein biomarker can be polynucleotide or polypeptide.
Dependent claims 84-86 further limit to the recited lengths and species.
Dependent claims 87 define mode of administrations with the divergent recited ones.
It the above claims all are variables, and none of the claims recite complete structure of claimed polypeptide, which is an active agent for the claimed method.
To support the above broadly claimed method or subject matter, exemplified or described claimed subject matter mostly with peptide 14 (SEQ ID NO: 1) and limited examples with peptide 13 (SEQ ID NO: 2), SEQ ID NO: 6 and 7. Additional sequences shown in Example 8 are theoretical since no data is shown. It appears that, in the shown data, mode of administration is limited topical, cell lines are limited to human fibroblasts and keratinocytes, and biomarkers limited to the recited makers in claim 32. No data or description is provided broadly claimed biomarkers, and polypeptide which can be up to 100 amino acid length.
So, the issue is in the scope of the broadly claimed subject matter in modulating all possible biomarkers by administering broadly claimed polypeptide in all possible cell lines with all possible mode of administrations. Specification failed to describe the nexus between shown and broadly claimed subject matter. In other words, the structure/function relationship for the claimed generic variables and claimed method is not described.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a divergency in the genus or broadly claimed subject matter, and if it expects unpredictability for the claimed method, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed method. In this case, at least protein chemistry is probably one of the most unpredictable areas of biotechnology and consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Similar reasoning can be applied to cell lines, biomarkers and mode of administrations etc. So, the absence of description with divergent species makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "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. 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" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP 2163 II(A)(3)(a)(ii).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described.
The question is with thousands of possible divergent species in all possible combinations, (i) did applicants provide enough description for making all possible peptides and biomarkers etc., with all possible mode of administrations? (ii) will the these be capable of retain its property? Based (i) and/or (ii), will a skilled person in the art understand the claimed invention?
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Not provided. The claimed genus of polypeptide can generate unlimited number of polypeptides. Specification merely describes a theoretical approach for the claimed method. Exemplified or described claimed subject matter is limited to mostly with peptide 14 (SEQ ID NO: 1) and limited examples with peptide 13 (SEQ ID NO: 2), SEQ ID NO: 6 and 7. Additional sequences shown in Example 8 are theoretical since no data is shown. It appears that, in the shown data, mode of administration is limited topical, cell lines are limited to human fibroblasts and keratinocytes, and biomarkers limited to the recited makers in claim 32. No data or description is provided broadly claimed biomarkers, and polypeptide which can be up to 100 amino acid length. The dosage range information have not been provided for the peptides. Further, it is completely generic.
So, the provided data is very limited.
Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
Fig.1 describes effect of polypeptides on progeria fibroblast cell number and senescence levels. Moreover, example 1 states that a total of 764 polypeptides were tested, among which 56 promoted a decrease in cellular senescence to below 75% that of the untreated control sample. So, the data is very divergent.
Fig. 2 describes senotherapeutic effects of polypeptides 13, 14, 15 and 16. So, it appears that peptide 14 is drastically different from others, though all these peptides have a common sequence of LKGI.
In Fig.3-13, shown data is limited to polypeptide 14. Markers information is not clear.
Fig.14 describes relative mRNA expression of recited biomarkers with polypeptides 13 and 14. Different markers show different levels, and some are not even significantly different from the control.
In Fig. 15, described data is limited polypeptide 14 and no comparison shown with other polypeptides.
Fig.16, describes SEQ ID NOs: 6-7, both have common sequence of LKGI.
Fig.17-38 limited to peptide 14. It appears that peptide 14 significantly reduced TYR expression and did not alter inflammation levels of IL6 and IL8.
So, as evidenced from the above description of drawings, it is clear that the claimed invention is not complete by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
At least, in the broadly claimed peptides, which can have all possible combination of amino acids in their sequences, a skilled person in the art cannot envision applicants claimed method, since protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted.
For example, Bowie et al (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
There is also unpredictability in the mode of administration, for example, Bruno et al [Ther Deliv, 2013 Nov, 4(11), 1443-1467] teach the following:
While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed. [See abstract and whole article].
In view of above evidences, applicants have claimed wide range of peptides and all possible combinations, and a skilled person in the art can expect unpredictability in the broadly claimed genus. There are no physical/chemical/structural features that applicants have tied to this property in a relevant teaching manner, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed peptides would be effective. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "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, whatever 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).
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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