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 .
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 (i.e., changing from AIA to pre-AIA ) 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.
Priority
This is a U.S. application filed on 12/15/2023 which claims priority to U.S. Provisional Application No. 63/587,266 filed on 10/02/2023 and to U.S. Provisional Application No. 63/433,391 filed on 12/16/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/06/2024 and 06/05/2024 have been received. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner, and all references are considered except where they were lined up.
Claim Rejections - 35 USC § 112(a)
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 1-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for human papilloma virus (HPV) negative head and neck cancer, and for IL-1β, FGF-2, IL-6 and IL-7, does not reasonably provide enablement for all types of cancer nor for all cytokines and interleukins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. In the instant case, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Specifically, the method for predicting the recurrence of any cancer, treating any cancer with an effective amount of any inhibitor of an interleukin and predicting the therapy outcome of any cancer is overly broad and is not well supported by the specification.
The current disclosure does not satisfy the enablement requirement for treating a patient with different types of cancer and whether any necessary experimentation is undue as discussed In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 recites a method for predicting cancer recurrence by obtaining lymphatic fluid from a site proximal to a tumor, measuring a level of a predetermined protein in the lymphatic fluid and predicting the recurrence of cancer on thebased oneasured level. Claim 14 further recites a method of therapeutic selection by obtaining lymphatic fluid from a site proximal to a tumor in a subject, measuring a level of a predetermined protein in the lymphatic fluid and selecting a treatment for the subject based on the measured level. And claim 22 recites a method of predicting a cancer therapy outcome by obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been treated for cancer by a neoadjuvant therapy and surgery, measuring a level of a predetermined protein in the lymphatic fluid, and determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the measured level. The specification does not provide enough support for an artisan to perform the above assays and methods without undue additional experimentation as described in in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998) as appropriate. See also MPEP § 2164.01(a) and § 2164.04.
The breadth of the claims:
Claim 1 is recited at a high level of generality by reciting a method of predicting any type of cancer by obtaining lymphatic fluid from a site proximal to any tumor, measuring a level of any predetermined protein in the lymphatic fluid and predicting the recurrence of any cancer based on the measured level of any protein. Claim 14 is also recited at a high level of generality because it is drawn to a method of therapeutic selection by obtaining lymphatic fluid from a site proximal to any tumor in any subject, measuring a level of any predetermined protein in the lymphatic fluid and selecting a treatment for the subject on the basis of the measured protein level. Claim 22 is further recited at a high level of generality because it is drawn to a method of predicting any cancer therapy outcome by obtaining lymphatic fluid from a site proximal to any tumor in any subject who has been treated for any cancer by any neoadjuvant therapy and surgery, measuring a level of any predetermined protein in the lymphatic fluid, and determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the measured level. Thus, claims 1, 14 and 22 are recited at a high level of generality.
The nature of the invention:
The invention is about three methods of predicting cancer recurrence, making a therapeutic selection and predicting cancer therapy outcome respectively. The first method is for predicting cancer recurrence by obtaining lymphatic fluid from a site proximal to a tumor, measuring a level of a predetermined protein in the lymphatic fluid and predicting the recurrence of cancer on the basis of the measured level. The second method is for therapeutic selection by obtaining lymphatic fluid from a site proximal to a tumor in a subject, measuring a level of a predetermined protein in the lymphatic fluid and selecting a treatment for the subject on the basis of the measured protein level. The third method is for predicting a cancer therapy outcome by obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been treated for cancer by a neoadjuvant therapy and surgery, measuring a level of a predetermined protein in the lymphatic fluid, and determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the measured protein level.
The state of the prior art:
Although there has been reports about treating one type of cancer as noted by Kazaz et al. for non-small lung cancer (Turk Thorac J 2017; 18: 101-7, Abstract), Morales-Betanzos et al. for human melanoma (MCP, Volume 16, Issue 10, October 2017, Pages 1705-1717, Abstract), and Li et al. for breast cancer (Cancer Cell 33, 187–201, February 12, 2018, Abstract), there is no prior art that describes the universal treatment of all types of cancer because of the complexity of cancer as a disease as noted by Gentles et al. (Cancer Res; 71(18) September 15, 2011, Page 5964, right column, second paragraph). Cancer is a variable disease, and its clinical manifestation and treatment differs even from one patient to another based on multiple factors and that makes treatment response vary greatly as noted by Yang et al. (Clinical pharmacology & Therapeutics, Volume 88, Number 1, July 2010). It is understood from the prior art that while there have been dramatic improvements in the treatment of patients with cancer, it remains a challenge for clinicians on how to tackle each type of cancer and how to offer the best treatment in each case. Last, there are still challenges in targeting interleukin-1 (IL-1) in solid tumors because of the reduction in overall leukocyte and, most importantly, neutrophil counts and the overall increased risk of fatal infections as noted by Gottschlich et al. (Cancers 2021, 13, 477, pages 1-17; page 5, last paragraph). Gottschlich noted that future studies need to include well-planned monitoring and detection strategies for infectious complications when treating a patient with IL-1 inhibitors (Page 5, last paragraph).
Furthermore, in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims of the instant application.
The level of one of ordinary skill:
Based on the complexity and unpredictability of cancer treatment as noted above by Gentles, Yang and Gottschlich, the level of a person having ordinary skill in the art is not high enough to treat all types of cancer. Gentles noted that cancer has been successfully eradicated in a Petri dish, but these results rarely translate to in vivo (Page 5963, left column, fifth paragraph). Gentles noted that tumor microenvironment play a role in deciding the behavior of cancer cells but is poorly understood (Page 5963, left column, fifth paragraph). Yang noted that there are fundamental challenges to cancer therapy because the consequences of target inhibition for protein networks in tumor and normal cells are unknown and considerable patient-to-patient variation is observed (Page 37, right column, first paragraph). And as noted above by Gottschlich, there is still a need to monitor and devise strategies to detect infectious complications in elderly patients who are being treated with inhibitors of IL-1 (Page 5, last paragraph).
Thus, a person who has ordinary skill in the art would not have been able to predict the relapse of every type of cancer with any protein and treat any type of cancer with any inhibitor of any cytokine or interleukin.
The level of predictability in the art:
There is a high level of unpredictability in the response of patients to cancer treatment as noted above by Yang. Yang noted that there are fundamental challenges to cancer therapy because responses to specific therapies are less dramatic and specific in patients than had been hoped, often because the consequences of target inhibition for protein networks in tumor
and normal cells are unknown and considerable patient-to-patient variation is observed (Page 37, right column, first paragraph). Furthermore, Gottschlich noted that there are unforeseen variations in the immune function of elderly patients because of the treatment effects over leukocyte counts (Page 11, left column, first paragraph).
The amount of direction provided by the inventor:
As discussed above, art acknowledges the complexity of cancer and thus the inventor needs to show how the method of the instant application will enable a skilled artisan to treat any type of cancer with any inhibitor of interleukins in any subject and how to assess the relapse of cancer and treatment outcome with any predetermined protein.
The specification only gives two examples on how to perform protein profiling of lymphatic samples from human papilloma virus (HPV) negative head and neck cancer patients and to identify increased levels of predetermined IL-1β, FGF-2, IL-6 and IL-7. Example 1 teaches characterizing the protein makeup of surgical drain fluid from 10 patients with HPV negative head and neck cancer (Pages 24-26, Example 1). Example 2 teaches conducting a proteomic study of lymph and plasma to perform the protein profiling from 44 HPV negative head and neck cancer patients (Pages 26-29, Example 2).
Examples 1 and 2 do not provide a plan or a method for how to treat every type of cancer with any inhibitor of interleukins in any subject and how to assess the relapse of cancer and treatment outcomes with any predetermined protein. Examples 1 and 2 only show protein profiling of predetermined IL-1β, FGF-2, IL-6 and IL-7 in patients with human papilloma virus (HPV) negative head and neck cancer. Thus, the specification of the instant application fails to address a method for treating any type of cancer with any inhibitor of interleukins in any subject and how to assess the relapse of cancer and treatment outcomes with any predetermined protein in a subject.
The existence of working examples:
There is a limited number of examples in the specification as noted above (Pages 24-26, Example 1; pages 26-29, Example 2). Example 1 is about protein profiling of surgical drain fluid from HPV negative head and neck cancer patients (Pages 25-26). Example 1 teaches that a significant increase in the levels of IL-1 beta, FGF-2, IL-6, and IL-7 in HPV negative head and neck cancer patients (Pages 25-26). Example 2 is about Protein profiling for lymph fluid and plasma specimens from a cohort of 44 HPV negative head and neck cancer patients (Pages 26-33). Example 2 teaches that lymph contains highly differentiated protein repertoires (Pages 29-29).
The examples are directed to protein profiling of lymphatic or drain fluids from HPV negative head and neck cancer patients. The examples do not teach treating all types of cancer with any inhibitor of interleukins in any subject and how to assess the relapse of any cancer and treatment outcomes with any predetermined protein.
Furthermore, there is no indication from the examples of the specification of the instant application that the broadly claimed method would work in any type of cancer with any inhibitor of any protein, cytokine or interleukin because the examples are only teaching protein profiling from HPV negative head and neck cancer patients. Thus, the specification does not provide guidance with respect to treating any type of cancer with any interleukin inhibitor and it cannot be assumed that the claimed method would work with any type of cancer and with any interleukin inhibitor and with any predetermined protein.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
With the lack of teaching in prior art regarding treating any cancer type and predicting the recurrence of any cancer type and predicting the outcomes of treating any cancer type, the PHOSITA is expected to face an unreasonable amount of experimentation. Furthermore, the complexity of cancer and the possible occurrence in different parts of the human body add another challenge to a PHOSITA or to a clinician.
Thus, the specification of the instant application does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims of the instant application. Consequently, claims 1-26 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for human papilloma virus (HPV) negative head and neck cancer and for IL-1β, FGF-2, IL-6 and IL-7, does not reasonably provide enablement for all types of cancer nor for all cytokines and interleukins.
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 therefore, subject to the conditions and requirements of this title.
Claims 1-26 are rejected under 35 U.S.C. 101 because the claimed invention is for a process or a method that is directed to at least one judicial exception without significantly more. The claims recite a mere collection of information in the form of data that is compared to a predetermined protein measurement from which the applicant or doctor will be able to predict the recurrence of cancer, select a therapy or predict cancer therapy outcome. Such an inference is not sufficient to transform the abstract idea of a mental process of comparing the measured protein level to a predetermined value, and a law of nature of correlating the protein concentration with subject’s diagnosis and response to treatment into a patentable application.
The claims are ineligible because they recite at least one judicial exception, i.e., an abstract idea of a mental process (comparing the measured protein level to a predetermined value), and a law of nature (correlating the protein concentration with subject’s diagnosis and response to treatment). Moreover, the claims as a whole do not integrate the judicial exceptions into a practical application nor do they provide an inventive concept.
Although there is a proposed treatment step in claims 14 and 22 it is a general step that does not add significantly more to the judicial exceptions of the instant application. Specifically, claim 14 recites “selecting a treatment for the subject on the basis of the measured level” which is a general treatment that encompass a wide range of therapeutic agents such as interleukin inhibitors, chemotherapy, radiation therapy or immunotherapy. And Claim 22 does not provide the treatment step after measuring the predetermined protein, and thus it does not integrate the judicial exceptions into a practical application. Moreover, claim 22 also recites “who has been treated for cancer by a neoadjuvant therapy and surgery” which is also a general treatment that does not specify what type of treatment is to be administered. Thus, the steps in claims 14 and 22 do not add significantly more to the judicial exceptions of the instant application, and therefore, the judicial exceptions are not integrated into a practical application.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?)
This part of the eligibility analysis evaluates whether the claim falls within any statutory category per MPEP 2106.03.
Example 43 of 2019 Revised Patent Subject Matter Eligibility Guidance (PEG) is particularly enlightening because the fact pattern of claim 1 of example 43 is most similar to the instant application claims (Subject matter eligibility | USPTO)
Regarding claim 1 of example 43 of the PEG and per Step 1, the claim is directed to a process, which is one of the statutory categories of invention as the claim recites “A treatment method comprising: (a) calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype; (b) administering a treatment to the patient having a non-responder phenotype.” (Step 1: YES).
Similarly, claim 1 of the instant application is also directed to a statutory class of a method for predicting cancer recurrence by obtaining lymphatic fluid from a site proximal to a tumor, measuring a level of a predetermined protein in the lymphatic fluid and predicting the recurrence of cancer based on the measured level (Step 1: YES).
And claim 14 of the instant application is directed to a statutory class of a method for therapeutic selection by obtaining lymphatic fluid from a site proximal to a tumor in a subject, measuring a level of a predetermined protein in the lymphatic fluid and selecting a treatment for the subject based on the measured level (Step 1: YES).
Also, claim 22 of the instant application is directed to a statutory class of a method of predicting cancer therapy outcome by obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been treated for cancer by a neoadjuvant therapy and surgery, measuring a level of a predetermined protein in the lymphatic fluid, and determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the measured level (Step 1: YES).
(Step 2A, Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?)
Claim 1 of example 43 of PEG recites judicial exceptions that are similar to claims 1, 14 and 22 of the instant application. Specifically, and per Step 2A, prong 1, claim 1 of example 43 of PEG recites the judicial exception of “calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype,” and according to broadest reasonable interpretation (BRI), an arithmetic calculation of a division is required to obtain the ratio of C11 to C13 that can be used to identify whether the patient has the non-respondent phenotype (i.e., the patient has a calculated ratio of 3:1 or greater and thus is not responding, or will not respond, to glucocorticoids). This limitation therefore recites a mathematical calculation. And the grouping of “mathematical concepts” in PEG includes “mathematical calculations” as an exemplar of an abstract idea. PEG Section I, 84 Fed. Reg. at 52. Thus, limitation (a) of claim 1 of PEG falls into the “mathematical concept” grouping of abstract ideas.
Similarly, claims 1, 14 and 22 of the instant application also recite a judicial exception of an abstract idea of a mental process of comparing the measured protein level to a predetermined value. Specifically, claims 11 14 and 22 recite “measuring a level of a predetermined protein in the lymphatic fluid”.
Also, limitation (a) of claim 1 of PEG describes a naturally occurring relationship between the ratio of C11 to C13 and the non-responder phenotype, and thus may also be considered to recite a law of nature.
Furthermore, claims 1, 14 and 22 also describe a naturally occurring relationship between protein concentration and subject’s diagnosis and response to treatment, and thus are considered to recite a law of nature. Specifically, claim 1 recites “predicting recurrence of the cancer on the basis of the measured level” and claim 14 recites “selecting a treatment for the subject on the basis of the measured level”. Claim 22 further recites “determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the measured level”.
Accordingly, limitation (a) of claim 1 of PEG recites three judicial exceptions (an abstract idea that falls within the mathematical concept, a mental process groupings in PEG, and a law of nature); whereas claims 1, 14 and 22 of the instant application also recite two judicial exceptions of an abstract idea of a mental process and a law of nature, and the analysis must therefore proceed to Step 2A Prong Two.
(Step 2A, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application?)
Per Step 2A, prong 2, claim 1 of example 43 of PEG and claims 1, 14 and 22 of the instant application as a whole do not integrate the recited judicial exception into a practical application. Specifically, this evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Besides the abstract idea, claim 1 of example 43 of PEG recites the additional element of “(b) administering a treatment to the patient having a non-responder phenotype”. Although this limitation indicates that a treatment is to be administered, it does not provide any information as to how the patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. In fact, this limitation is recited at such a high level of generality that it does not even require a doctor to take the calculation step’s outcome (the patient’s phenotype) into account when deciding which treatment to administer, making the limitation’s inclusion in this claim at best nominal. Thus, limitation (b) of example 43 of PEG fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, limitation (b) of example 43 of PEG does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Similar to claim 1 of example 43 of PEG, claims 1, 14 and 22 of the instant application do not have additional elements that would integrate the judicial exceptions cited above into a practical application. The claims have steps of measuring a level of a protein to compare to predetermined value to predict the recurrence of cancer, to select a treatment or to determine the pharmacodynamic effect of the neoadjuvant therapy, and these steps do not integrate the judicial exceptions into a practical application because they are data gathering steps to use in the measurement and comparison, which do not add a meaningful limitation to the methods as they are insignificant extra-solution activity. These steps do not integrate the judicial exceptions into a practical application because they do not amount to more than the judicial exceptions themselves, analogous to Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 80, 84, 101 USPQ2d 1961, 1968-69, 1970 (2012). Furthermore, the claims do not act on or use the judicial exceptions in any further steps as required by MPEP 2106.04(d). In the instant case, the doctor is not required to perform any further action based on the assessment of a subject for cancer recurrence, whereas claims 14 and 22 only recommend providing a general treatment to the subject. Therefore, claims 1, 14 and 22 of the instant application do not integrate the judicial exceptions into a practical application.
(Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?)
Per Step 2B, claim 1 of example 43 of PEG and claims 1, 14 and 22 of the instant application do not recite additional elements that amount to significantly more than the judicial exception. Specifically, this part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. As explained with respect to Step 2A Prong Two, claim 1 of example 43 of PEG recites a single additional element in limitation (b), which does not require any particular application of the recited calculation and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept (Step 2B: NO). The claim is not eligible.
Similarly, claims 1, 14 and 22 of the instant application simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, such as measuring the level of a protein for example with a commercially available assay such as with ELISA (Specification, page 26, third paragraph, “measure tumor-predictive
proteins in SDF (e.g., in both the 12-plex & 45-plex panels) via an assay with labeled antibodies
such as an ELISA or lateral flow assay or the Luminex system”). Furthermore, the claims themselves are recited at a high level of generality in which any assay can be used as the measurement method for claims 1, 14 and 22.
Thus, claims 1, 14 and 22 are not eligible and are rejected under 35 USC 101.
Regarding claims 2-5, 8-9 and 23-24, the claims recite the type of protein which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 6, the claim determines the surgical site which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 7, the claim recites the source of the lymphatic fluid and the number of measurements which do not integrate the judicial exception into a practical application, nor do they amount to significantly more.
Regarding claim 10, the claim recites the measuring step which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 11, the claim further recites deriving a tumor mutational burden which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 12, the claim recites the quantification assay which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 13, the claim recites the protein of IL-1β and its level which do not integrate the judicial exception into a practical application, nor do they amount to significantly more.
Regarding claim 15, the claim recites when to obtain the lymphatic fluid which does not integrate the judicial exception into a practical application, nor does it amount to significantly more. The claim further provides a general treatment which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claims 16-18, the claims provide general treatment which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 19, the claim provides non-specific inhibitors of IL-1β which do not integrate the judicial exception into a practical application, nor do they amount to significantly more.
Regarding claim 20, the claim provides a general treatment step which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 21, the claim recites the protein as IL-1β and provides a general treatment which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 25-26, the claims recite a general treatment which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-9 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Broggi et al. (J. Exp. Med. 2019 Vol. 216 No. 5 1091–1107).
Claim 1 Recites:
“A method of predicting cancer recurrence, the method comprising:
obtaining lymphatic fluid from a site proximal to a tumor;
measuring a level of a predetermined protein in the lymphatic fluid; and
predicting recurrence of the cancer on the basis of the measured level”.
Regarding claim 1, Broggi teaches a method of predicting cancer recurrence from metastatic melanoma patients (Abstract; page 1092, left column, third paragraph, “we hypothesized that lymph carries important tumor-derived factors that reflect the tumor microenvironment and may allow patient stratification or help predict response to therapy.”; page 1092, left column, fourth paragraph, “We show not only that the lymphatic exudate is drastically enriched in secreted tumor-associated factors, but also that they contain proteomic signatures that may be used to differentiate early from late stages of metastatic spread”). Broggi also teaches obtaining lymphatic fluid from a site proximal to a melanoma tumor (1092, left column, fourth paragraph, “Here we collected postoperative lymphatic leak, hereafter referred to as lymphatic exudate, from metastatic melanoma patients undergoing lymphadenectomy (LAN)”). Broggi further teaches measuring a level of a predetermined protein in the lymphatic fluid (Page 1092, right column, second paragraph, “Proteomic profiles of lymphatic exudate EVs revealed that most of the proteins were derived from the cytoplasm”; page 1092, right column, “However, the lymphatic exudate was dramatically enriched in melanoma-associated proteins such as LDH, S100B, and S100A8 compared with plasma … where they were undetectable”). And Broggi teaches predicting recurrence of the metastatic melanoma based on the measured level (Page 1092, left column, third paragraph, “we hypothesized that lymph carries important tumor-derived factors that reflect the tumor microenvironment and may allow patient stratification or help predict response to therapy”).
Regarding claim 2, Broggi teaches that the protein is an inflammatory protein (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”).
Regarding claim 3, Broggi teaches that the protein is a cytokine (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”).
Regarding claim 4, Broggi teaches that the protein is an interleukin (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”)
Regarding claim 5, Broggi teaches that the protein is IL-1beta (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”)
Regarding claim 6, Broggi teaches that the site is a surgical site of removal of the melanoma tumor (1092, left column, fourth paragraph; page 1102, left column, fourth paragraph, “Lymph can be collected after sentinel node biopsy during the surgical procedure or in already diagnosed metastatic melanoma patients who undergo a radical LAN, where additional LNs surrounding the sentinel node are removed”).
Regarding claim 7, Broggi teaches that the lymphatic fluid is obtained as drain fluid that drains from the surgical site and is obtained during and after surgical removal of the melanoma tumor (1092, left column, fourth paragraph; page 1102, left column, fourth paragraph, “Lymph can be collected after sentinel node biopsy during the surgical procedure or in already diagnosed metastatic melanoma patients who undergo a radical LAN, where additional LNs surrounding the sentinel node are removed”). Broggi teaches that the method comprises making a first measurement in fluid obtained during the removal and a second measurement in fluid obtained after the surgical removal of the melanoma tumor ((1092, left column, fourth paragraph; page 1102, left column, fourth paragraph, “Lymph can be collected after sentinel node biopsy during the surgical procedure or in already diagnosed metastatic melanoma patients who undergo a radical LAN, where additional LNs surrounding the sentinel node are removed”).
Regarding claim 8, Broggi teaches measuring levels of a plurality of proteins in the lymphatic fluid (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”). Regarding claim 9, Broggi teaches that the proteins include cytokines (Page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”).
Regarding claim 12, Broggi teaches that the measuring step includes performing an assay to quantify the level of the protein the lymphatic fluid, wherein the assay includes binding labeled antibodies to the proteins (Page 1100, Figure 6, “C) Expression of S100 proteins in EVs isolated from lymphatic exudate of melanoma patients as analyzed by mass spectrometry”; page 1098, left column, first paragraph, “fluorescent EVs were observed in draining lymphatic vessels”; “The fluorescent secondary antibodies were provided by Molecular Probes”).
Claims 14-15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Zevallos et al. (US 2022/0389520 A1, priority to Jun. 7, 2021).
Claim 14 recites:
“A method of therapeutic selection, the method comprising:
obtaining lymphatic fluid from a site proximal to a tumor in a subject;
measuring a level of a predetermined protein in the lymphatic fluid; and
selecting a treatment for the subject on the basis of the measured level”.
Regarding claim 14, Zevallos teaches a method of therapeutic selection [0004]. Zevallos further teaches obtaining lymphatic fluid from a site proximal to an HPV-positive Oropharyngeal tumor in a subject (Abstract; [0045]; [0085]). Zevallos also teaches measuring a level of a predetermined protein in the lymphatic fluid (Abstract; claim 3; Fig. 1; [0061]; [0078]). And Zevallos teaches selecting a treatment for the subject based on the measured level ([0004]; [0048]).
Regarding claim 15, Zevallos teaches that the lymphatic fluid is obtained after surgery to remove the tumor, and the treatment is selected for adjuvant therapy ([0079]; [0085]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art (PHOSITA) to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Broggi et al. (J. Exp. Med. 2019 Vol. 216 No. 5 1091–1107) as applied to claim 1 above, and further in view of Casey et al. (US 2021/0002719 A1).
Claim 10 recites:
“The method of claim 1, wherein the measuring step further includes sequencing
circulating tumor DNA (ctDNA) from the lymphatic fluid to identify a number of tumor
mutations in the ctDNA”.
Regarding claim 10, the previous teachings of Broggi are previously discussed.
Regarding claim 10, Broggi does not teach that the measuring step further includes sequencing circulating tumor DNA (ctDNA) from the lymphatic fluid to identify a number of tumor mutations in the ctDNA.
Regarding claim 11, Broggi does not teach deriving a tumor mutational burden (TMB) from the number of tumor mutations, wherein a high TMB is predictive of recurrence.
Regarding claim 10, Casey teaches that the measuring step further includes sequencing circulating tumor DNA (ctDNA) from the lymphatic fluid to identify a number of tumor mutations in the ctDNA (Abstract).
Regarding claim 11, Casey teaches deriving a tumor mutational burden (TMB) from the number of tumor mutations, wherein a high TMB is predictive of recurrence [0031].
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the sequencing method of Casey with the melanoma cancer recurrence prediction method of Broggi because Casey methods assessed the tumor evolution to select appropriate therapy for the patient to achieve a response to treatment [0002-0003]. A PHOSITA would have had a reasonable expectation of success in combining the methods of Casey and Broggi based on the methods being in the field of cancer detection and treatment.
It would have been obvious for a PHOSITA to use the sequencing method of Casey with the melanoma cancer prediction method of Broggi to provide the most effective treatment to the patient.
Claims 13 is rejected under 35 U.S.C. 103 as being unpatentable over Broggi et al. (J. Exp. Med. 2019 Vol. 216 No. 5 1091–1107) as applied to claim 1 above, and further in view of Aimone et al. (US 2022/0025036 A1).
Claim 13 recites:
“The method of claim 1, wherein the protein is IL-1β and the method include predicting
recurrence of the tumor when the IL-1β is present at a concentration of at least 30 pg/mL in the
lymphatic fluid”.
Regarding claim 13, the previous teachings of Broggi are previously discussed.
Moreover, regarding claim 13, Broggi teaches that the protein is IL-1β and the method includes predicting recurrence of the melanoma tumor (Abstract; page 1092, left column, third paragraph, “we hypothesized that lymph carries important tumor-derived factors that reflect the tumor microenvironment and may allow patient stratification or help predict response to therapy”; page 1092, left column, fourth paragraph, “We show not only that the lymphatic exudate is drastically enriched in secreted tumor-associated factors, but also that they contain proteomic signatures that may be used to differentiate early from late stages of metastatic spread”; page 1093, Figure 1, “(D) Inflammatory cytokines: IL-6, -8, -1β, -4, and -10, and TNF-α”).
Regarding claim 13, Broggi does not teach predicting recurrence of the tumor when the IL-1β is present at a concentration of at least 30 pg/mL in the lymphatic fluid.
Regarding claim 13, Aimone teaches that IL-1β is present at a concentration that is barely detectable in a healthy person and further notes that the levels of IL-1β are higher than normal in a patient with cancer that has a partial inflammatory basis [0049]. Aimone teaches that tumor cells in the bone are associated with increases in IL-1β and high levels of IL-1β in tumor cells promotes angiogenesis, further stimulates metastases [0349]. Thus, associating the IL-1β concentration of at least 30 pg/mL with tumor recurrence is a clear example of routine optimization within the prior art conditions or through routine experimentation because Aimone clearly noted the association of increases in IL-1β levels with tumor cells in the bone [0349].
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the IL-1β inhibitor of Aimone with the metastatic melanoma tumor recurrence method of Broggi because Aimone treats cancers that have at least a partial inflammatory basis [0005] and further notes the association of high levels of IL-1β concentration with tumors in the bone and metastasis [0349]. A PHOSITA would have had a reasonable expectation of success in combining the methods of Aimone and Broggi based on the methods being in the field of cancer detection and treatment.
It would have been obvious for a PHOSITA to use the IL-1β inhibitor of Aimone with the metastatic melanoma tumor recurrence method of Broggi to provide the most effective treatment to the patient
Furthermore, in order to properly support a rejection on the basis that an invention is the result of "routine optimization", the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail. The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range. See In re Stepan, 868 F.3d 1342, 1346, 123 USPQ2d 1838, 1841 (Fed. Cir. 2017). See also In re Van Os, 844 F.3d 1359,1361,121 USPQ2d 1209, 1211 (Fed. Cir. 2017) ("Absent some articulated rationale, a finding that a combination of prior art would have been ‘common sense’ or ‘intuitive’ is no different than merely stating the combination ‘would have been obvious.’"); Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355, 1362, 119 USPQ2d 1822 (Fed. Cir. 2016) ("[R]eferences to ‘common sense’ … cannot be used as a wholesale substitute for reasoned analysis and evidentiary support … ."). In the instant case, a skilled artisan would have been motivated to combine the IL-1β treatment method of Aimone with the metastatic melanoma tumor recurrence method of Broggi because Aimone noted the association of high levels of IL-1β with tumors in the bone and metastasis [0349].
Claims 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Zevallos et al. (US 2022/0389520 A1) as applied to claim 14 above, and further in view of Aimone et al. (US 2022/0025036 A1).
Claim 16 recites:
“The method of 14, wherein the protein is a pro-inflammatory cytokine, and the measured
level is used to select an adjuvant therapy”.
Regarding claims 16-21, the teachings of Zevallos are previously discussed.
Regarding claim 16, Zevallos does not teach that the protein is a pro-inflammatory cytokine and the measured level is used to select an adjuvant therapy. Regarding claim 17, Zevallos does not teach that the selected treatment comprises an antibody. Regarding claim 18, Zevallos does not teach that the selected treatment comprises an interleukin Inhibitor. Regarding claim 19, Zevallos does not teach that the interleukin inhibitor comprises the IL-1beta inhibitor anakinra, canakinumab, or rilonacept. Regarding claim 20, Zevallos does not teach that the selected treatment comprises the interleukin inhibitor in combination with a treatment comprising chemotherapy, radiation, or Immunotherapy. Regarding claim 21, Zevallos does not teach that the protein is IL-1β and the selected treatment comprises an IL-1β inhibitor.
Regarding claim 16, Aimone teaches that the protein is a pro-inflammatory cytokine [0033]; [0124] and the measured level is used to select an adjuvant therapy ([0049]; [0153-0154]).
Regarding claim 17 Aimone teaches that the selected treatment comprises an antibody (Abstract).
Regarding claims 18-19, Aimone teaches that the selected treatment comprises an interleukin Inhibitor, and that the interleukin inhibitor comprises the IL-1beta inhibitor anakinra, canakinumab, or rilonacept (Abstract; [0075]).
Regarding claim 20, Aimone teaches that the selected treatment comprises the interleukin inhibitor in combination with a treatment comprising chemotherapy, radiation, or an immunotherapy [0124].
Regarding claim 21, Aimone teaches that the protein is IL-1β, and the selected treatment comprises an IL-1β inhibitor (Abstract; [0075]).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine IL-1β inhibitor of Aimone with the therapeutic selection method of Zevallos because Aimone treats cancers that have at least a partial inflammatory basis [0005] and further notes the association of high levels of IL-1β concentration with tumors in the bone and metastasis [0349]. A PHOSITA would have had a reasonable expectation of success in combining the methods of Aimone and Zevallos based on the methods being in the field of cancer detection and treatment.
It would have been obvious for a PHOSITA to use the IL-1 β inhibitor of Aimone with the therapeutic selection method of Zevallos to provide the most effective treatment to the patient.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Derouane et al. (Cancers 2022, 14, 3876, pages 1-31) in view of Zevallos et al. (US 2022/0389520 A1).
Claim 22 recites:
“A method of predicting a cancer therapy outcome, the method comprising:
obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been
treated for cancer by a neoadjuvant therapy and surgery;
measuring a level of a predetermined protein in the lymphatic fluid; and
determining a pharmacodynamic effect of the neoadjuvant therapy on the basis of the
measured level”.
Regarding claim 22, Derouane teaches a method of predicting breast cancer therapy outcome (Abstract). Derouane teaches determining a pharmacodynamic effect of the neoadjuvant therapy based on the measured level (Abstract; page 4 of 31, first paragraph, “highlight the future perspectives that could lead to the better prediction of response to NAC in early breast cancer patients, focusing on the current biomarkers used in clinical decision making”).
Regarding claim 22, Derouane does not teach obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been treated for cancer by a neoadjuvant therapy and surgery. Also, Derouane does not teach measuring the level of a predetermined protein in the lymphatic fluid.
Regarding claim 22, Zevallos teaches obtaining lymphatic fluid from a site proximal to a tumor in a subject who has been treated for oropharyngeal squamous cell carcinoma by a neoadjuvant therapy and surgery (Abstract; [0009]]. Zevallos further teaches measuring the level of a predetermined protein in the lymphatic fluid (Abstract; claim 3; Fig. 1; [0061]; [0078].
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the detection method of Zevallos with Derouane’s prediction method of breast cancer therapy because Zevallos method assesses a post-surgical cancer patient for surgery outcomes and potential complications [0004. A PHOSITA would have had a reasonable expectation of success in combining the methods of Zevallos and Derouane based on the methods being in the field of cancer detection and treatment.
It would have been obvious for a PHOSITA to use therapeutic selection method of Zevallos with Derouane’s predictive model of breast cancer therapy outcome to provide the most effective treatment to the patient.
Claims 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Derouane et al. (Cancers 2022, 14, 3876, pages 1-31) and Zevallos et al. (US 2022/0389520 A1) as applied to claim 22 above, and further in view of Aimone et al. (US 2022/0025036 A1).
Claim 23 recites:
“The method of claim 22, wherein the protein is a cytokine or an interleukin”.
Regarding claims 23-26, the teachings of Derouane and Zevallos are previously discussed.
Regarding claim 23-24, Derouane does not teach that the protein is a cytokine or an interleukin, and that the protein is IL-1β. Regarding claim 25, Derouane does not teach that the neoadjuvant therapy comprises an IL-1β inhibitor.
Regarding claim 26, Derouane does not teach that the neoadjuvant therapy comprises an IL-1β inhibitor in combination with a treatment comprising chemotherapy, radiation, or immunotherapy.
Regarding claim 23-24, Aimone teaches that the protein is a cytokine or an interleukin and that the protein is IL-1β (Abstract; [0033]; [0075]; [0124]).
Regarding claim 25, Aimone teaches that the neoadjuvant therapy comprises an IL-1β inhibitor (Abstract; [0075]).
Regarding claim 26, Aimone teaches that the neoadjuvant therapy comprises an IL-1β inhibitor in combination with a treatment comprising chemotherapy, radiation, or an immunotherapy [0124].
It would have been obvious for a PHOSITA before the effective filing date of the application to combine IL-1β inhibitor of Aimone with the combined therapeutic and predictive methods of Zevallos and Derouane because Aimone treats cancers that have at least a partial inflammatory basis [0005] and further notes the association of high levels of IL-1β concentration with tumors in the bone and metastasis [0349]. A PHOSITA would have had a reasonable expectation of success in combining the methods of Aimone, Zevallos and Derouane based on the methods being in the field of cancer detection and treatment.
It would have been obvious for a PHOSITA to use the IL-1 β inhibitor of Aimone with the therapeutic selection method of Zevallos and Derouane’s predictive model of breast cancer therapy outcome for example to provide the most effective treatment to the patient.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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