DETAILED ACTION
Status of the Claims
Claims 1-29 are currently pending and are the subject of this Office Action.
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 08/24/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 8 and 29 are objected to as being dependent upon a rejected base claim, but would be free allowed if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Appropriate correction is required.
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 9-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
Claim 9 recites a method for “diagnosing idiopathic pulmonary fibrosis (IPF) using exosomal biomarkers” and is directed to one or more of a law of nature, a natural phenomenon, a product of nature, and an abstract idea. Specifically, the “diagnosing idiopathic pulmonary fibrosis (IPF)” step in the claim represents the natural correlation between measured exosomal biomarkers and a disease state (i.e. IPF), this correlation being a law of nature and/or natural phenomena as per MPEP 2106.04(b)(I). In addition, the “using the protein signature to determine if the at least two exosomal protein biomarkers for IPF are elevated compared to a predetermined baseline level” and “identifying a protein signature for at least two exosomal protein biomarkers for IPF” steps in the claim each encompasses embodiments (e.g., selecting and comparing) that represent a mental process, which is an abstract idea as per MPEP 2106.04(III)(A). Therefore, the claim recites one or more judicial exceptions as per Prong One of the revised Step 2A analysis from the 2019 Revised Patent Subject Matter Eligibility Guidance issued Jan. 7, 2019 in the Federal Register Vol. 84, No. 4. The same Guidance requires analysis of Prong Two, which is whether the claim recites additional elements that integrate the exception(s) into a practical application of that exception(s). In the instant case, the additional element(s) is/are “extracting a human subject sample containing EVs” and “performing proteomic analysis of plasma extracellular vesicles (EVs)”, and do not represent a practical application of the exception(s), since both steps are merely data-gathering steps needed to practice the natural correlation and thus are insignificant extra-solution activity, as defined and discussed in MPEP § 2106.05(g). Therefore, the claims must further be analyzed to identify additional elements to determine whether the claim as a whole amounts to significantly more than the judicial exception (i.e. Step 2B of the analysis).
For claim 9, the additional elements consist of “extracting a human subject sample containing EVs” and “performing proteomic analysis of plasma extracellular vesicles (EVs)”, do not represent a practical application of the exception(s), since these steps constitute routine, convention, and well-understood activities known in the industry at the time of the invention, specified as a high level of generality, and therefore are not enough to qualify as “significantly more” when recited with the judicial exception of the claim. This is consistent with the observation by Applicant at para [0054] of the specification, which states “[d]ue to their high abundance in accessible body fluids, … in the past decade, EVs have become a reliable source for biomarker discovery”, citing two review articles:
Boukouris et al., “Exosomes in bodily fluids are a highly stable resource of disease biomarker,” Proteomics Clin. Appl. 2015: 9(3-4):358-67
Huda et al., “Potential Use of Exosomes as Diagnostic Biomarkers and in Targeted Drug Delivery: Progress in Clinical and Preclinical Applications,” ACS Biomater Sci. Eng. 2021: 7(6):2106-49
Further, as discussed in MPEP 2106.05(g), when the additional steps (i.e., other than the judicial exception(s)) are limitations that are well known or amount to necessary data gathering steps, they are considered to be insignificant extra-solution activities does not amount to an inventive concept. Note that the Supreme Court in Parker v. Flook, 437 U.S. 584, 588-89, 198 USPQ 193, 196 (1978) reasoned that "[t]he notion that post-solution activity, no matter how conventional or obvious in itself, can transform an unpatentable principle into a patentable process exalts form over substance.” This is conclusion is equally true both when considering the steps individually and as an ordered combination.
Claims 10, 13-14, 17-18, and 21 merely further define the protein biomarkers and source of the sample, claims 12 and 21 add conventional and well-understood high-resolution computed tomography and general screening for IPF, claim 15 limits the size of the EVs, and claim 16 recites the use of mass spectrometry in data gathering, however, none of these steps, alone or in combination with claim 9, qualify as “significantly more” nor do not they constitute a practical application for the identified judicial exceptions at least because they are well known and conventional, and/or amount to necessary data gathering steps.
Claim 11 merely further defines the judicial exception of IPF diagnosis being not determinable using high-resolution computed tomography, and claim 19 recites claim 9 “further comprising differentiating idiopathic pulmonary fibrosis (IPF) from other interstitial lung diseases (ILDs) using exosomal protein biomarkers that are elevated more than a baseline specific to other ILDs other than IPF”, which itself is reasonably a judicial exception as encompassing embodiments of data analysis that can be performed mentally, for example, by comparing levels of biomarkers in a sample to a baseline reference.
Similar to claim 9, claim 22 recites a method for screening for IPF using exosomal protein biomarkers, consisting of data gathering (according to step 1) in the form of extracting/producing a subject sample and performing proteomic analysis of the plasma EVs, identifying a protein signature, and comparing measured levels to baseline reference levels. Claim 23 (similar to claim 11) merely further defines the judicial exception of IPF diagnosis being not determinable using high-resolution computed tomography. Therefore, for analogous reasoning as above, these claims are also not patent eligible.
Claim 28 recites a method of treating a subject having IPF by first diagnosing the subject with IPF using the same steps as above, followed by “administering a therapeutic for IPF to the subject”. Here, the step of diagnosing IPF using measured EV biomarkers is reasonably a judicial exception, representing the natural correlation between measured biomarkers and a disease state (i.e. IPF); this correlation being a law of nature and/or natural phenomena as per MPEP 2106.04(b)(I). The additional step of “administering a therapeutic for IPF” to the subject needs to be evaluated to determine if it reasonably integrates the judicial exception into a practical application. Please see MPEP 2106.04(d)(2) for a detailed discussion regarding the role of additional elements in integrating a judicial exception into a practical application by effecting a particular treatment or prophylaxis. As per this section of the MPEP, the particularity or generality of the treatment should be considered as relevant factors in the analysis. In the present case, the step of generically “administering a therapeutic for IPF” to the subject is not particular and thus encompasses all applications of the judicial exception. This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the judicial exception(s) into a practical application.
Claims 24-27 recite a protein biomarker panel (and a kit thereof) comprising at least two of the listed exosomal protein biomarkers and “instructions for performing the method of claim 1”. Regarding the protein biomarkers, these reasonably include the naturally occurring proteins of the listed proteins and are therefore drawn to a judicial exception, specifically to a product of nature. See MPEP 2106.04(b)-(c) for detailed discussion of products of nature and their identification as a law of nature or natural phenomenon. Here, the protein biomarkers encompass embodiments that reasonably are either (i) naturally occurring, or (ii) not naturally occurring, but not having markedly different characteristics as compared to their naturally occurring counterparts.
Regarding the included instructions of the claims, which are, by definition, non-naturally occurring, MPEP 2106.04(c)(I)(A) states:
Where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to "a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt"), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception.
In the present claims, the instructions do not reasonably endow the products of nature with any markedly different characteristics so as to transform them into something that is patent eligible.
Furthermore, regarding printed instructions included as part of a kit, and in accordance with MPEP § 2111.05, while “a claim must be read as a whole, USPTO personnel may not disregard claim limitations comprised of printed matter ... [h]owever, USPTO personnel need not give patentable weight to printed matter absent a new and unobvious functional relationship between the printed matter and the substrate”, citing In re Lowry, 32 F.3d 1579, 1583-84, 32 USPQ2d 1031, 1035 (Fed. Cir. 1994). In MPEP § 2111.05(I)(B), citing In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864, it is noted that “in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals”. Therefore, in the instant claim, the recited instructions do not make the claims patent eligible.
For further information, please see the latest revision of MPEP § 2104-2106 {Patent Subject Matter Eligibility Under 35 U.S.C. 101}, including MPEP § 2106.04 {Eligibility Step 2A: Whether a Claim is Directed to a Judicial Exception} and 2106.05 {Eligibility Step 2B: Whether a Claim Amounts to Significantly More}, as well as any additional guidance on Subject Matter Eligibility, provided on the USPTO website at
https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility.
Claim Rejections – 35 U.S.C. 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Velázquez-Enríquez et al.
Claims 1-2, 4-7, and 22-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Velázquez-Enríquez et al. (Biomedicines, 2021, 9:1058, published 08/20/2021).
Regarding claims 1 and 6, Velázquez-Enríquez discloses a method of preparing a human subject sample containing EVs and exosomes comprising:
extracting a human subject sample (e.g., samples are from fibroblast cells lines from IPF patients and healthy donors, as per the Abstract);
producing a sample from said human subject sample, wherein the human subject sample contains EVs and a subpopulation enriched in exosomes (e.g., as per the 2.2. Isolation of Extracellular Vesicles and Protein Extraction section on pp. 2-3, noting that the reference specifically enriches for smaller EVs/exosomes, for example, by removal of larger EVs such as apoptotic bodies using centrifugation); and
performing proteomic analysis of plasma extracellular vesicles (EVs) in the sample containing EVs and the subpopulation enriched in exosomes (e.g., as per the 2.4. Label-Free Quantitative Proteomic Analysis section on pp. 3-5).
Regarding claims 2 and 7, Velázquez-Enríquez discloses the above method, further comprising quantifying levels of the at least three of High mobility group box protein 1 (HMGB1), Aldolase A (ALDOA), and Talin-1 (TLN1) in plasma extracellular vesicles (EVs) in the sample containing EVs and the subpopulation enriched in exosomes (e.g., as per Table S1).
Regarding claim 4, Velázquez-Enríquez discloses the above method, wherein the human subject sample is not blood serum, not broncho-alveolar lavage fluid (BALF), not inflammatory cells, and/or not hyperplasic epithelial cells (e.g., samples are from fibroblast cells lines from IPF patients and healthy donors, as per the Abstract).
Regarding claim 5, Velázquez-Enríquez discloses the above method, wherein the EVs are 50-200 nm in diameter (e.g., from ultracentrifugation as per the 2.2. Isolation of Extracellular Vesicles and Protein Extraction section on pp. 2-3).
Regarding claim 22, Velázquez-Enríquez discloses the above method, comprising identifying a protein signature for at least two protein biomarkers selected from the group consisting of: SFTPB, ALDOA, HMGB1, CALML5, and TLN1 in the sample containing EVs and the subpopulation enriched in exosomes; and
using the protein signature to determine if the at least two biomarkers protein biomarkers are elevated compared to a predetermined baseline level for the at least two biomarkers (e.g., as per Table S1).
Regarding claim 23, since no HRCT was performed by the reference (samples were purchased from cell lines), then no definitive diagnosis can be made based on such a test.
Regarding claims 24-27, Velázquez-Enríquez discloses a protein biomarker panel comprising at least two exosomal protein biomarkers selected from the group consisting of SFTPB, ALDOA, HMGB1, CALML5, and TLN1 (e.g., as per Table S1). Regarding the limitation of “instructions for performing the method of claim 1” included as part of a kit, and in accordance with MPEP § 2111.05, while “a claim must be read as a whole, USPTO personnel may not disregard claim limitations comprised of printed matter ... [h]owever, USPTO personnel need not give patentable weight to printed matter absent a new and unobvious functional relationship between the printed matter and the substrate”, citing In re Lowry, 32 F.3d 1579, 1583-84, 32 USPQ2d 1031, 1035 (Fed. Cir. 1994). In MPEP § 2111.05(I)(B), citing In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864, it is noted that “in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals”. Therefore, in the instant claim, the recited instructions do not distinguish over the prior art as instantly applied.
Karimi et al.
Claims 1-7 and 24-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Karimi et al. (Cellular and Molecular Life Sciences, 2018, 75:2873–2886).
Regarding claims 1 and 6, Karimi discloses a method of preparing a human subject sample containing EVs and exosomes comprising:
extracting a human subject sample (e.g., samples are from healthy donors, as per the Blood collection and processing section);
producing a sample from said human subject sample, wherein the human subject sample contains EVs and a subpopulation enriched in exosomes (e.g., “supernatant was subjected to ultracentrifugation at 118,000×gavg (Type 70 Ti rotor, k-factor 133.7, Beckman Coulter) for 2.5 h to pellet smaller EVs such as exosomes” as per p. 2875); and
performing proteomic analysis of plasma extracellular vesicles (EVs) in the sample containing EVs and the subpopulation enriched in exosomes (e.g., as per the Mass Spectrometry section on pp. 2876-2877).
Regarding claims 2 and 7, Karimi discloses the above method, further comprising quantifying levels of the at least three of High mobility group box protein 1 (HMGB1), Aldolase A (ALDOA), and Talin-1 (TLN1) in plasma extracellular vesicles (EVs) in the sample containing EVs and the subpopulation enriched in exosomes (e.g., as per Supplementary Table 1).
Regarding claims 3-4, Karimi discloses the above method, wherein the human subject sample is blood plasma containing plasma extracellular vesicles and is not blood serum, not broncho-alveolar lavage fluid (BALF), not inflammatory cells, and/or not hyperplasic epithelial cells (e.g., plasma as per the Blood collection and processing section and Fig. 1).
Regarding claim 5, Karimi discloses the above method, wherein the EVs are 50-200 nm in diameter (e.g., as per Fig. 2-3).
Regarding claims 24-27, Karimi discloses a protein biomarker panel comprising at least two exosomal protein biomarkers selected from the group consisting of SFTPB, ALDOA, HMGB1, CALML5, and TLN1 (e.g., as per Supplementary Table 1). Regarding the limitation of “instructions for performing the method of claim 1” included as part of a kit, and in accordance with MPEP § 2111.05, while “a claim must be read as a whole, USPTO personnel may not disregard claim limitations comprised of printed matter ... [h]owever, USPTO personnel need not give patentable weight to printed matter absent a new and unobvious functional relationship between the printed matter and the substrate”, citing In re Lowry, 32 F.3d 1579, 1583-84, 32 USPQ2d 1031, 1035 (Fed. Cir. 1994). In MPEP § 2111.05(I)(B), citing In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864, it is noted that “in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals”. Therefore, in the instant claim, the recited instructions do not distinguish over the prior art as instantly applied.
Conclusion
No claims are allowed.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684