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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informality: the Sequence Incorporation by Reference paragraph is missing, as noted above.
Appropriate correction is required.
Claim Objections
Claims 7-8 are objected to because of the following identical informality: a comma should be inserted after “The DNA aptamer according to claim 6.” Appropriate correction is required.
Claim 10 is objected to because of the following informality: in the contacting step, the phrase “in vitro” should be presented in italics to match the format of the phrase as used in the preamble. Appropriate correction is required.
Claim 11 is objected to because of the following informalities: a comma should be inserted after “The method of claim 10” and in line 4, “mCRP” should read “monomeric C-reactive protein” to match the format of the protein name used throughout the claim set. Applicant may also state “monomeric C-reactive protein (mCRP)” earlier in the claim set, and then refer to mCRP in subsequent recitations. Appropriate correction is required.
Claim 12 is objected to because of the following informality: in lines 2-3, “surface plasmon resonance assay, capillary electrophoresis-laser-induced fluorescence assay” should read “a surface plasmon resonance assay, a capillary electrophoresis-laser-induced fluorescence assay.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Enablement and 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 6-14 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not reasonably provide enablement for the design and use of any aptamer meeting the criteria of instant claim 6. Accordingly, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected to, to make and/or use the invention commensurate in scope with the claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Each of these factors is discussed below.
Nature of the Invention
Claims 6-9 are drawn to a DNA aptamer of a particular sequence, where said sequence has variable nucleotides and a particular function in that the aptamer must bind to a monomeric C-reactive protein.
Claims 10-12 are drawn to a method of detecting a monomeric C-reactive protein using the DNA aptamer of claim 6.
Claims 13-14 are drawn to a kit for detecting monomeric C-reactive protein that includes the DNA aptamer of claim 6.
The claimed methods are classified in the unpredictable arts of molecular biology and biochemistry.
Breadth of the Claims
Claim 6 is very broad in that it encompasses many potential nucleotide sequences.
Claim 7 requires a particular function of the DNA aptamer, but does not explicitly limit the potential nucleotide sequences.
Claim 8 specifies three potential sequences for the DNA aptamer that do not include variable nucleotide sequences.
Claim 9 does not narrow or further define the DNA aptamer sequence of claim 6.
As noted above, claims 10-12 recite a method involving the DNA aptamer of claim 6, and do not limit the sequence of said DNA aptamer.
Similarly, claims 13-14 recite a kit involving the DNA aptamer of claim 6, and do not limit the sequence of said DNA aptamer.
Level of Skill in the Art
The ordinary artisan typically holds at least a master’s degree has several years of experience.
State of the Prior Art & Unpredictability
Concerning the claimed invention, what was (and is) unpredictable in the art is whether a particular DNA aptamer encompassed by SEQ ID NO: 1 could perform the function specified in instant claim 6 – namely, binding to monomeric C-reactive protein.
No prior art could be found that specifically teaches DNA aptamers comprising SEQ ID NO: 1, nor SEQ ID NOs: 2-4, which are recited in claim 8 and read on the nucleotide sequence of the DNA aptamer of instant claim 6.
However, the prior art does generally teach DNA aptamers that bind to monomeric C-reactive protein.
Wang et al. (Anal Bioanal Chem, 20111) teaches the determination of an aptamer that is capable of binding to a monomeric CRP but not a pentameric CRP (Abstract). This aptamer was made of RNA (see page 1310, “Materials and Methods”) and was found to not form a persistent bond with pentameric CRP while strongly bonding with monomeric CRP (page 1313, “CRP-RNA-aptamer complex formation” and Figure 2). The RNA aptamer used was based on an aptamer previously known in the art (page 1310, column 1, para. 2).
Huang et al. (Biosensors and Bioelectronics, 2010; cited in Applicant’s IDS) teaches a method for rapidly screening aptamers that can bind to CRP (Abstract). A DNA library of random single-stranded DNA sequences was developed, and then were tested for their specificity to CRP (see Figure 1). This selection process was done multiple times, and the authors used a modified version of a typical SELEX process (see page 1766, “Conclusions” and Table 1).
Lee et al. (US 2017/0175169 A1; cited in Applicant’s IDS) teaches methods for identifying biomarkers and diagnosing chronic diseases (Abstract). These methods can involve the use of aptamers, where initial aptamer selection can involve a process similar to that of Huang in that a large pool of potential aptamers is brought in contact with a target, and aptamers that bind to the target are then further analyzed (Figure 2). These aptamers can then be used to aid in disease diagnosis (Figures 4 and 5, for example). The aptamers considered by Lee may be random, or be partially random and have particular positions designated with certain nucleotides (paras. 77 and 96). The reference teaches that up to 410 aptamer sequences can be in a potential pool para. 77).
Thus, while general methods of aptamer selection are known in the prior art, particularly for detecting known targets (such as CRP, or monomeric CRP even more specifically), these are generally based on pools of random sequences that are then further refined into more specific aptamers. The prior art does not appear to point out known patterns in the aptamers that would make them more likely to be specific for CRP, and so the generation of sequences with specificity to monomeric CRP would be as unpredictable as general aptamer selection for the ordinary artisan.
Guidance in the Specification and Examples
Generally, the specification discusses the claimed invention. Specifically, pages 3 and 7-8 detail the use of SEQ ID NOs: 1-4 with the same DNA aptamer functions as detailed in the instant claims, but provide no data or support for the function of the claimed aptamer. Figures 1-4 and 8 utilize DNA aptamers AmC2, AmC3, and AmC4, which are later explained to be SEQ ID NOs: 5-7, and are not claimed (see the instant specifications pages 5-6 for the figures captions, as well as Example 1 on page 10 for the descriptions of each AmC aptamer).
In the working examples, only AmC2, AmC3, and AmC4 are used. It is noted that these sequences contain SEQ ID NOs: 2-4, but also include primer sequences at their 5’ and 3’ ends. Thus, while these sequences do comprise SEQ ID NO: 1, they also include additional nucleotides. While these sequences are shown to bind specifically to mCRP and not pCRP (see page 14 of the instant specification), the same is not shown for SEQ ID NOs: 2-4, nor any other aptamer that would consist of SEQ ID NO: 1. Example 3 of the instant specification compared AmC2 to a prior art aptamer, but this prior art aptamer is not a DNA aptamer (and is the aptamer used by Wang and described above; see page 19 of the instant specification).
It is noted that when primer sequences are removed from aptamers, binding properties can be altered. For example, Yang et al. (RSC Adv., 2018) conducted a study examining aptamers with different primer sequences, and found that when primer sequences were removed from several aptamers, dissociation constants increased, which lead to a decrease in binding affinity. However, no substantial change in affinity was observed for other aptamers upon primer removal (pages 19071-19072, joining para.). Thus, in view of the unpredictability in the art discussed here and above, it is not clear that the results discussed by Applicant would extend over the full scope of the claimed invention. Specifically, it is not clear that SEQ ID NOs: 2-4 would retain the binding properties of SEQ ID NOs: 5-7 upon removal of the primer sequences, and so it is not clear that SEQ ID NOs: 2-4 would meet the functional limitations established by instant claims 6 (i.e. binding to a monomeric CRP) and 7 (i.e. not binding to pentameric CRP).
The Examiner suggests explicitly claiming SEQ ID NOs: 5-7 (which were the aptamers stated to be used in the working examples), and/or providing a declaration that details evidence that SEQ ID NOs: 2-4 retain the claimed binding function(s). While this would not provide adequate written description or enablement over the entire genus encompassed by the claims, claims limited to these aptamers would be considered allowable.
Quantity of Experimentation
The ordinary artisan would have to conduct a very large quantity of highly unpredictable experimentation before being able to successfully practice the full scope of the claimed methods. Specifically, the ordinary artisan would have to determine which of each of the different DNA aptamers encompassed by SEQ ID NO: 1 are capable of functioning as claimed in instant claim 6. Based on the teachings in the art, this would be an inventive and unpredictable undertaking, requiring extensive experimentation in which there is no guarantee of success. The large quantity of experimentation and its unpredictability constitute undue experimentation.
Conclusion
In view of the foregoing, it is clear that the specification fails to enable the full scope of the claimed methods, and claims 6-14 are rejected under 35 U.S.C. 112(a) for failing to comply with the enablement requirement.
Claims 6-14 are also 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.
As noted above in the enablement rejection, Applicant has only provided three examples of DNA aptamers in their specification that are encompassed by SEQ ID NO: 1 (SEQ ID NOs: 2-4), and has provided no evidence that any of these sequences, or any other sequence encompassed by SEQ ID NO: 1, can fulfill the functional requirement of instant claim 6. The sequences shown to fulfill the functional requirement of instant claim 6, SEQ ID NOs: 5-7, while they do comprise SEQ ID NO: 1, also include additional nucleotides and are not explicitly claimed. Therefore, Applicant has not demonstrated the use of any species encompassed by SEQ ID NO: 1 that would read on both the structure and function of the genus of DNA aptamers presented in instant claim 6, and in light of this and the unpredictability in the prior art described above in the enablement rejection, the ordinary artisan would not have recognized that the inventor was in possession of the claimed invention in view of the disclosure of the application as filed.
Consideration Under 35 USC 101
Claims 6-9 and 13-14 are directed to products involving the claimed DNA aptamer. These claims are not rejected under 35 USC 101 because the claimed DNA aptamer is considered markedly different from a corresponding natural DNA sequence, as the aptamer has different functional characteristics than a corresponding DNA sequence (e.g. binding to a specific protein target). Claims 10-12 are directed to a method involving the use of the claimed DNA aptamer. These claims are not rejected under 35 USC 101 as the prior art does not teach SEQ ID NO: 1 as a standalone DNA aptamer sequence.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 Applicant has provided a different version of this reference, from NIH Public Access, in their IDS. The final edited form of the article from Analytical and Bioanalytical Chemistry is cited here, and a copy of this version has been provided with this Office Action.