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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/24/2026 has been entered.
DETAILED ACTION
Claims 1, 3-6, 9, 11-13, 15, 17, 19-21, 54-57, and 97-98 are pending. Claims 1, 3-6, 9, 11-13, and 54-57 are withdrawn. Claims 2, 7-8, 10, 14, 16, 18, 22-53, and 58-96 are canceled. Claims 15, 17, 19-21, and 97-98 are under examination on their merits.
Response to Arguments
Applicant's arguments filed 4/24/2026 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims under 35 U.S.C. 101 on the grounds that the steps recited in claim 15 are significantly more than a natural law (Arguments, paragraph 1 on page 5). Applicant argues that prior to Applicant’s invention, no one understood that detecting a fragment of a substrate of TPP-1 in a cyst fluid sample was sufficient to know that TPP-1 was present in the sample and that the cyst was characterized by high-grade dysplasia or invasive cancer (Arguments, paragraph 3 on page 7). Applicant concludes based on this that claim 15 and its dependent claims recite something significantly more than a mere natural law (Arguments, paragraph 3 on page 7). Applicant compares the current claims to subject matter eligibility example in which using a porcine antibody to detect a human protein was not well-understood, routine, and conventional activity (Arguments, paragraph 2 on page 6) as well as Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042, 104 7-49 (Fed. Cir. 2016) in which the novel order of and sequence of freezing and thawing conferred subject matter eligibility (Arguments, paragraph 2 on page 7).
In response, these arguments are not persuasive. The presence or absence of TPP-1 in the mucinous cyst based on the underlying disease state is the natural phenomenon. These are not additional elements within the claim. Step 2B of the subject matter eligibility flowchart (see MPEP 2106 part (III) and 2106.04 part (II)(A)) applies to the additional elements of the claim (not the judicial exception). The natural phenomenon cannot itself be the inventive concept of the claim.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See [0046], [0120], [0123], [0129]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities: exp[ osure to an enzyme (such as a serin protease). See [0069].
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 15, 17, 19-21, and 97-98 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.
Claim 15 recites “detecting an amount of the fragment of the substrate and correlating the amount to TPP-1 presence, absence, or a biologically significant quantity in a sample from the subject” in lines 6-8. It is unclear whether the biologically significant quantity is a quantity of TPP-1 in a sample from the subject or some other quantity. Applicant may consider amending the claim to recite “detecting an amount of the fragment of the substrate and correlating the amount to the presence or absence of TPP-1 or a biologically significant quantity of TPP-1 in a sample from the subject.”
Similarly, claim 17 recites “correlating the amount of the fragment to TPP-1 presence, absence, or a biologically significant quantity,” which is problematic for the same reasons discussed above.
Claim 17 is further indefinite because it is unclear whether the method further comprises exposing a control sample to an enzymatically effective amount of the substrate and detecting an amount of the fragment of the substrate.
Claim 17 is indefinite because the claim recites “as compared to a control value” and “an amount of fragment of the substrate detected after exposure of a control sample to the enzymatically effective amount of the substrate.” The claim has more than one reasonable interpretation. In one interpretation, the control value is the amount of fragment of the substrate detected after exposure of a control sample to the enzymatically effective amount of the substrate. In a second interpretation, the control value is not limited to the amount of fragment of the substrate detected after exposure of a control sample to the enzymatically effective amount of the substrate. Thus, the ambiguity lies in the fact that the claim requires both a control value and a control sample but does not recite any relationship between the control value and the control sample.
Claim 19 recites “the exposure for a time period sufficient to cause cleavage of the substrate into one or a plurality of fragments.” It is unclear how the substrate can be cleaved into one fragment, as by definition, cleaving a substrate necessarily produces at least two fragments.
Claims 17, 19-21, and 97-98 are also rejected for being dependent on a rejected base claim and failing to remedy the issue set forth above.
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 15, 17, 19-21 and 97-98 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 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 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.
Claim 15 recites a method of diagnosing a subject with a mucinous cyst of the pancreas characterized by high-grade dysplasia or invasive cancer comprising exposing a cyst fluid sample from the subject to an enzymatically effective amount of a substrate specific to the tripeptidyl-peptidase 1 (TPP1) for a time period sufficient to catalyze a reaction between the TPP-1 and the substrate to produce a fragment of the substrate..
The broadest reasonable interpretation of a substrate specific to TPP1 encompasses proteins, peptides, small molecules, and other compounds that TPP1 recognizes (binds to) and cleaves.
The person of ordinary skill in the art would not have recognized that the inventors, at the time the application was filed, had possession of the claimed genus of substrates specific to the tripeptidyl-peptidase 1.
The specification defines “specific for” as meaning that the binding affinity of a substrate to a target such as tripeptidyl peptidase is statistically higher than the binding affinity of the same substrate to a generally comparable, but non-target amino acid sequence ([0063]).The specification defines “substrate cleaved in the presence of” as a molecule comprising an amino acid sequence recognized by TPP1 and cleaved at the amino acid sequence ([0060]). Note that the present claim language (“specific to”) matches neither definition. The specification discloses further in [0060] that If the enzyme detected is a lysosomal peptidase protease (such as TPP1), the substrate comprises X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8
wherein X1 is D;
X2 is E, F, W, orY;
X3 is G, D, M, or R;
X4 is Y, F, W, L, or M;
X5 is Y, M, L, A, F, or S;
X6 is L, T or R;
X7 is Q or Y; and
X8 is H.
Kondo et al. (Peptides 76 (2016): 80-86) teaches the substrate NH2-RWFFIQ-EDDnp is highly selective for TPP-1 compared to the generally used substrate NH2-AAF-MCA (Abstract). Fig. 4 depicts the selectivity of TPP-1 for various peptides. Fig. 5 presents the activity of TPP-1 on the NH2-RWFFIQ-EDDnp substrate in the presence of various protease inhibitors.
Tian et al. (Journal of Biological Chemistry 281.10 (2006): 6559-6572) performs a substrate-specificity study of the enzyme TPP-1 for a wide range of potential biological substrates using fluorescence and mass spectrometry (Abstract). However, all of the substrates in the library are peptides (Fig. 1-4).
In summary, although the prior art teaches several species of peptide substrates specific for TPP-1, the prior art does not teach any species of small molecules or compounds that are specific for TPP-1.
Applicant may consider amending claim 15 by adding "wherein the substrate specific to TTP-1 is an amino acid sequence recognized by TPP-1."
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 15, 17, 19-21, and 97-98 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
The claims are drawn to a method of diagnosing a subject a with mucinous cyst of the pancreas characterized by high-dysplasia or invasive cancer by detecting a presence, absence, or biologically significant quantity of TPP-1 in a cyst fluid sample from the subject indirectly by detecting an amount of a fragment of a substrate specific to TPP-1. The claimed method is directed to the judicial exception of a natural phenomenon: the amount of TPP-1 in a subject with a mucinous cyst of the pancreas characterized by high-grade dysplasia or invasive cancer of the pancreas. This judicial exception is not integrated into a practical application because the output of the method is purely information (the underlying disease state of the subject) rather than, for example, a particular treatment of the disease. The additional elements recited in claim 15 amount to insignificant extra-solution data gathering activity. The additional elements recited in the dependent claims are either insignificant extra-solution activity or abstract mental processes. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they are directed to the naturally occurring phenomenon, an abstract idea involving mental process, and/or recite elements that are well-understood, routine, and conventional.
The claimed invention seeks to correlate an indirect detection of TPP-1 from a subject sample to diagnose the subject with a mucinous cyst of the pancreas characterized by high-grade dysplasia or invasive cancer. Thus, the claimed invention correlates a biomarker occurrence in a subject with the disease of the pancreas, which is a natural phenomenon. Claim 15 further recites “exposing the sample to an enzymatically effective amount of a substrate specific to TPP-1 for a time period sufficient to catalyze a reaction between the TPP-1 and the substrate; and detecting an amount of the fragment of the substrate and correlating the amount to TPP-1 presence, absence, or a biologically significant quantity in a sample from the subject” which is insignificant extra-solution data gathering activity that seeks to indirectly determine an amount of TPP-1 in the sample. Thus, claim 15 does not recite significantly more than the natural phenomenon and remains directed to the natural phenomenon.
Claim 17 recites “wherein correlating the amount of the fragment to TPP-1 presence, absence or a biologically significant quantity comprises calculating a score corresponding to a normalized amount of TPP-1, as compared to a control value, in the sample based upon the amount of the fragment compared to an amount of fragment of the substrate detected after exposure of a control sample to the enzymatically effective amount of the substrate, wherein the substrate is an internally quenched FRET substrate, and production of the fragment of the substrate yields a fluorescent signal” which concerns performing a mathematical calculation that can be practically performed in the human mind and insignificant extra-solution data gathering activity. Thus, this step is directed to an abstract idea in the “mental process” grouping and insignificant extra-solution data gathering activity.
Claim 19 recites “correlating the amount of fragment of the substrate after the exposure for a time period sufficient to cause cleavage of the substrate into one or a plurality of fragments with a likelihood that the subject has a benign, pre-malignant, or malignant growth of the pancreas, wherein if the amount of fragment of the substrate is equal to or greater than three times the amount of fragment of the substrate found after exposure to the control sample, then the subject is diagnosed with a pre-malignant or malignant cyst of the pancreas; and wherein if the amount of fragment of the substrate is less than or equal to 1 times the amount of fragment of the substrate found after exposure to the control sample, then the subject is diagnosed with a benign, mucinous cyst of the pancreas.” This claim concerns performing a mathematical calculation that can be practically performed in the human mind. Thus, this step is an abstract idea in the “mental process” grouping.
Claim 20 recites “the TPP-1 comprises an amino acid sequence comprising SEQ ID NO: 10” which is directed to correlating indirectly detecting a TPP-1 biomarker to a disease state. Additionally, human TPP-1 has an amino acid sequence that is 100% identical to SEQ ID NO: 10 (see Appendix A of the Non-Final Action mailed on 2/13/2025 for human TPP-1 and Appendix B of the Non-Final Action mailed on 2/13/2025 for sequence alignments; of record). This is a natural process, and thus claim 20 is directed to the judicial exception of a natural phenomenon.
Claim 21 recites “detecting a biologically significant quantity of gastricsin and/or cathepsin E, individually or collectively, in the sample,” which is directed to a natural phenomenon: the natural correlation of the quantity of gastricsin and/or cathepsin E biomarkers to a disease state. Thus, claim 21 is directed to the judicial exception of a natural phenomenon.
Claim 97 recites the substrate is bound to a solid surface. Claim 98 recites the solid surface is a plastic plate or dish comprising a vessel within which the substrate is bound. These additional elements are well-understood, routine, and conventional activity. For example, Halling et al. (Current opinion in biotechnology 16.4 (2005): 385-392) teaches the catalytic action of an enzyme on an immobilized substrate (Figure 1(c)). The substrate can be immobilized in a plate comprising one or more vessels (see Fig. 3).
Thus, the claimed method is directed to the natural phenomenon of the quantity of TPP-1 in a subject having a mucinous cyst of the pancreas characterized by high-grade dysplasia or invasive cancer. The additional claim elements recited in claim 15 and the dependent claims do not amount to more than the judicial exception for the reasons discussed above. Therefore, the claims are directed to a natural phenomenon judicial exception without significantly more.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
