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 .
Remarks
In response to communications sent July 7, 2023 claim(s) 35-58 are pending in this application; of these claims 35 and 57 are in independent form. Claims 1-34 are cancelled.
Response to Amendment
The preliminary amendments to the claims and abstract that were filed July 7, 2023 are acknowledged and have been entered into the record.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
At this point in prosecution, the claims are assumed to have the priority date of the foreign priority documents, January 8, 2021 because similarity between the priority document specification and the specification of the U.S. application, albeit based on cursory review.
Information Disclosure Statement
The Information Disclosure Statement(s) is/are acknowledged and the references contained therein have been considered by the Examiner. This includes the Information Disclosure Statements(s) filed on: August 29, 2023.
Claim Objections
Claims 39-41 are objected to because of the following informalities: The list “20, 21, 22, 23, 24 25” omits the word “or”. Claims 40-41 are objected to because they depend on claim 39. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
1. Claims 35-56 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 prediction of “frailty,” “arthritis,” “cognitive impairment,” “kidney cancer,” “early stage squamous cell lung cancer,” and “SARS-CoV-2 related complications,” does not reasonably provide enablement for the broad set of conditions “clinical and/or treatment outcome in a human subject at risk of clinical condition” in claim 35. Nor does the specification reasonably provide enablement for the sets of multiple conditions listed in the dependent claims. 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. The considerations (“Wands Factors”) are:
(A) Breadth of the claims: the claims include the preamble of claim 35 that breaths “life and vitality” to the steps of the claims. The preamble suggests that the prediction from the method is intended to be used for a medical purpose for which reliability and accuracy is sought.
(B) Nature of the invention: Applicant’s specification describes several species of the claimed genus in the Example sections. Based experimental outcomes are provided as evidence in the form of case studies. The section headings the case studies are stated in general terms while the case study recite specific medical conditions applicable to the patients of the case studies.
(C) State of the prior art: The claims have been taught by at least one reference in the prior art, but it is not routine and conventional to carry out the combination of steps (i) and (ii) of the method of the independent claim 35.
(D) Level of one of ordinary skill: one of ordinary skill could review simple medical statistics to assess the quality of a diagnostic to determine whether predictions are significant based on clinical or preclinical data.
(E) Level of predictability in the art: The prior art includes some medical conditions that are predictable, some that are a heterogenous set of genetically diverse diseases with heterogenous levels of predictability (e.g., cancers), and some that are difficult to predict (e.g., Alzheimer’s disease).
(F) The amount of direction provided by the inventor: The inventor provides case studies as examples for specific patients with specific medical conditions. The case studies have a small sample size preventing a meaningful test of statistical significance. Nevertheless, the specification provides biological motivation and context for why clinical predictability would be expected based on qualitative understanding of biology.
(G) The existence of working example: See (B) and (F) above.
(H) Quantity of experimentation: There is a large quantity of experimentation needed to use the invention to predict and provide a medical use for all of conditions, broad and narrow, that are encompassed and listed in the claims.
2. Claim 58 is 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 prediction of “frailty,” “arthritis,” “cognitive impairment,” “kidney cancer,” “early stage squamous cell lung cancer,” and “SARS-CoV-2 related complications,” does not reasonably provide enablement for the broad set of conditions “worsening of the medication condition” [that is an unspecified medical condition] or “first clinical manifestations of increasing disease or severity” in claim 58. 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. The considerations (“Wands Factors”) are:
(A) Breadth of the claims: the claim includes a treatment that has the effect of being precautionary or to treat the first clinical manifestations of a condition.
(B) Nature of the invention: Applicant’s specification describes several species of the claimed genus in the Example sections. Based experimental outcomes are provided as evidence in the form of case studies. The section headings the case studies are stated in general terms while the case study recite specific medical conditions applicable to the patients of the case studies.
(C) State of the prior art: The claim has been taught by at least one reference in the prior art, but it is not routine and conventional to carry out the combination of involving IL-6 and cell counts of neutrophils.
(D) Level of one of ordinary skill: one of ordinary skill could review simple medical statistics to assess the quality of a diagnostic to determine whether predictions are significant based on clinical or preclinical data.
(E) Level of predictability in the art: The prior art includes some medical conditions that are predictable, some that are a heterogenous set of genetically diverse diseases with heterogenous levels of predictability (e.g., cancers), and some that are difficult to predict (e.g., Alzheimer’s disease).
(F) The amount of direction provided by the inventor: The inventor provides case studies as examples for specific patients with specific medical conditions. The case studies have a small sample size preventing a meaningful test of statistical significance. Nevertheless, the specification provides biological motivation and context for why clinical predictability would be expected based on qualitative understanding of biology.
(G) The existence of working example: See (B) and (F) above.
(H) Quantity of experimentation: There is a large quantity of experimentation needed to use the invention to predict and provide a medical use for all of conditions, broad and narrow, that are encompassed and listed in the claims.
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 57-58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) a mathematical calculation. This judicial exception is not integrated into a practical application because claim 57 only recites the mathematical calculation in the steps of the body of the claim, while claim 58 does not recite a particular treatment or prophylaxis. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claim 57 recites no additional elements beyond the abstract idea and claim 58 recites only the element of treatment and prophylaxis at a high level of generality that is well-understood, routine, and conventional. Regarding the conventionality of claim 58, see the precedential case Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018).
Claim 57: A method of treating a human subject characterized by predictive score S P>0 indicating that the human subject has an increased risk of an adverse clinical and/or treatment outcome, wherein predictive score is calculated using a Theta Heaviside function using at least a normalized salivary IL-6 value (Ñ IL-6) and a normalized salivary neutrophil value (Ñ NP), wherein the normalized salivary IL-6 value (Ñ IL-6) and normalized salivary value (Ñ NP) are determined according to a scoring algorithm (the preamble describes a treatment of a particular type of human subject as an intended use, but is not a positively recited step), comprising the steps of
a) assigning a predictive IL-6 score Ñ IL-6=0, if the salivary IL-6 concentration is lower than or equal to the normalization value of IL-6 (mathematical calculation),
b) calculating Ñ IL-6 as the ratio of salivary IL-6 concentration:IL-6 normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ IL-6, for a salivary IL-6 concentration which is greater than the IL-6 normalization value (mathematical calculation),
c) assigning a predictive neutrophil (NP) score Ñ NP=0, if the salivary neutrophil concentration is lower than or equal to the normalization value for salivary neutrophils (mathematical calculation),
d) calculating Ñ NP as the ratio of salivary neutrophil concentration: salivary neutrophil normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ NP, for a salivary neutrophil concentration which is greater than the IL-6 normalization value, and wherein the predictive score (S P) is calculated as S P=Ñ NP+Ñ IL-6 (mathematical calculation).
Claim 58: The method of treating a human subject according to claim 57, wherein the treatment is a precautionary treatment prior to the worsening of the medical condition, or wherein the treatment is chosen to treat the first clinical manifestations of an increasing disease severity or activity (this element is not a mathematical calculation and not a judicial exception; however, it does not meet the standard for being a particular treatment or prophylaxis as noted in the precedential case Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018); instead, the claims recite a treatment or prophylaxis at a high-level of generality).
Note that claims 35-56 are not rejected under 35 USC § 101. The claims are in statutory class of a method and recite a mathematical calculation. However, the combination of steps (i) and (ii) in claim 35 is a combination of elements that is not well-understood, routine and conventional these two steps are not a judicial exception. Instead, the elements were interpreted as:
(i) determining the salivary concentration of Interleukin-6 (IL-6) in a salivary sample of said human subject (this is an additional element beyond the abstract idea because Applicant’s Specification at page 8 line 34 to page 9 line 7 suggest that the “determining” step involves an assay kit and is not a mental determination); and
(ii) determining the concentration of salivary neutrophils in said salivary sample of said human subject (this is an additional element beyond the abstract idea because Applicant’s Specification at page 9 lines 13-34 suggest that the “determining” step involves an assay) …
The Examiner searched for whether there is evidence that combining steps (i) and (ii) is well-understood, routine and conventional. The references US 20210247403 A1 (“Arvey”) and US 20100179072 A1 (“Yount”) each describe steps (i) and (ii) in combination. Arvey teaches the elements as noted in the rejection under 35 USC § 102 below; Yount teaches the combination of elements because the specification recites IL-6 as part of a list and the document mentions neutrophil measurements; and US 20200148760 A1 (“Matsuoka”) discusses inferring neutrophil levels using gene expression markers without measuring the neutrophil count directly.
However, Arvey and Yount discuss the combination of elements as part of a large permutation of lists of possible combinations. Therefore, the particular species of steps (i) and (ii) are not emphasized in those references so as to suggest conventionality. Furthermore, the Matsuoka reference does not measure the neutrophil count directly, but instead infers the neutrophil presence using expression markers.
In addition, the following references do not combine IL-6 measurement and neutrophil cell counts into a single score in a way that suggests the practice is routine and conventional. Instead the assays are performed separately in separate contexts:
Panneer Selvam, Niranzena, and Jayachandran Sadaksharam. "Salivary interleukin‐6 in the detection of oral cancer and precancer." Asia‐Pacific Journal of Clinical Oncology 11.3 (2015): 236-241.
Domnich, Maksim, et al. "Oral neutrophils: underestimated players in oral cancer." Frontiers in immunology 11 (2020): 565683.
Sahibzada, Haafsa Arshad, et al. "Salivary IL-8, IL-6 and TNF-α as potential diagnostic biomarkers for oral cancer." Diagnostics 7.2 (2017): 21.
Koizumi, Tomonobu, Vivek Shetty, and Masaki Yamaguchi. "Salivary cytokine panel indicative of non-small cell lung cancer." Journal of International Medical Research 46.9 (2018): 3570-3582.
Claim Rejections - 35 USC § 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 (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.
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)(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.
Claim(s) 35, 39-40, 42-55, and 57-58 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20210247403 A1 (“Arvey”).
As to claim 35, Arvey teaches a method of predicting the clinical and/or treatment outcome in a human subject at risk of clinical condition (Arvey Abstract: predicting immune health) comprising
(i) determining the salivary concentration of Interleukin-6 (IL-6) in a salivary sample of said human subject (Arvey Para [0003]: measuring the IL-6 amount in saliva); and
(ii) determining the concentration of salivary neutrophils in said salivary sample of said human subject (Arvey Para [0006]: determining a neutrophil amount from the sample described in Para [0003]; concentration fractions may be used in place of cell counts according to Para [0041]), wherein the method further comprises calculating a predictive score for the calculation (Arvey Para [0007]: calculating a predicted immune health) of which the at least two biomarkers salivary concentration of IL-6 (Arvey Para [0007]: IL-6 measurement for the score) and concentration of salivary neutrophils are used (Arvey Para [0006]: calculating amount of neutrophils; ; concentration fractions may be used in place of cell counts according to Para [0041]) and wherein the normalized salivary IL-6 value (Ñ IL-6) and normalized salivary neutrophil value (Ñ NP) (Arvey Para [0043]: values compared to reference exaptation values for the immune index calculation) are used in a Theta Heaviside function wherein the normalized salivary IL-6 value (Ñ IL-6) and normalized salivary value (Ñ NP) are determined according to a scoring algorithm (Arvey Figure 14B: the scores are kept positive in an index, which is the functional purpose of using the step function that is the Thea Heaviside function to avoid negative values as components of the sum calculation), comprising the steps of
i) assigning a predictive IL-6 score Ñ IL-6=0, if the salivary IL-6 concentration is lower than or equal to the normalization value of IL-6 (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference; the claimed limitation is at once envisaged from these three possibilities),
ii) calculating Ñ IL-6 as the ratio of salivary IL-6 concentration:IL-6 normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ IL-6, for a salivary IL-6 concentration which is greater than the IL-6 normalization value (Arvey Para [0055]: normalizing a biomarker value against an expected reference value),
iii) assigning a predictive neutrophil (NP) score Ñ NP=0, if the salivary neutrophil concentration is lower than or equal to the normalization value for salivary neutrophils (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference; the claimed limitation is at once envisaged from these three possibilities),
iv) calculating Ñ NP as the ratio of salivary neutrophil concentration: salivary neutrophil normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ NP, for a salivary neutrophil concentration which is greater than the IL-6 normalization value (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference), and wherein
the predictive score (S P) is calculated as SP=Ñ NP+Ñ IL-6 (Arvey Para [0143]: the predictive index score may be calculated by combining scores from distinct aspects of immune health).
As to claim 39, Arvey teaches the method according to claim 35, wherein the predictive score is calculated using one or more additional biomarkers (Arvey Para [0003]: additional biomarkers), wherein the predictive score SP is calculated as
S P =Ñ NP +Ñ IL-6+Σ i=1 n Ñ( i),
wherein Ñ(i), is the predictive score of the one or more additional biomarker, wherein n is from 1 to 20, 21, 22, 23, 24 25, (Arvey Para [0143]: the predictive index score may be calculated by combining scores from distinct aspects of immune health) and wherein the normalized value (Ñ(i)) is determined according to a scoring algorithm calculation (Arvey Para [0007]: calculating a predicted immune health), comprising the steps of
i) assigning a predictive Ñ(i)=0, if the concentration of said biomarker in said salivary sample is lower than or equal to the normalization value of said biomarker (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference; ; the claimed limitation is at once envisaged from these three possibilities),
ii) calculating Ñ(i) as the ratio of said salivary biomarker (i) concentration: biomarker(i) normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ(i), for a salivary biomarker(i) the concentration of which is greater than respective normalization value of said biomarker (i) (Arvey Para [0055]: normalizing a biomarker value against an expected reference value).
As to claim 40, Arvey teaches the method according to claim 39, wherein the one or more additional biomarker is selected from the group comprising interleukin receptor antagonist, interleukin-1 beta (Arvey Para [0003]: IL-1beta), interleukin-7 (Arvey Para [0003]: IL-7), interleukin-8 (Arvey Para [0003]: IL-8), interleukin-10 (Arvey Para [0003]: IL-10), interleukin-13 (Arvey Para [0003]: IL-13), colony stimulating factor 3 (this element is claimed in the alternative and does not need to be mapped), C-X-C motif chemokine ligand 10 (Arvey Para [0003]: CXCL10), C-C motif chemokine ligand 3 (this element is claimed in the alternative and does not need to be mapped), C-C motif chemokine ligand 11 (this element is claimed in the alternative and does not need to be mapped), interferon-gamma (this element is claimed in the alternative and does not need to be mapped), tumor necrosis factor-alpha (Arvey Para [0003]: TNFalpha), alpha-synuclein (this element is claimed in the alternative and does not need to be mapped), amyloid beta 1-42, protein t-TAU, matrix metalloproteinase-8, CA125, TPS, CA19-9, CEA, CA 15-3, or SCC (these elements are claimed in the alternative and do not need to be mapped).
As to claim 42, Arvey teaches the method according to claim 35, wherein the clinical condition is a decrease in organ function, wherein the decrease in organ function is one of lung function, heart function, renal function (Arvey para [0089]: a decrease in lung, renal, or heart function characteristic of cancer), cardiovascular function, musculoskeletal function, endocrine function, gastrointestinal function, or neurological function (these elements are claimed in the alternative and do not need to be mapped).
As to claim 43, Arvey teaches the method according to claim 35, wherein the clinical condition is medical complication, wherein the medical complication is one of renal failure (Arvey para [0089]: a decrease in lung, renal, or heart function characteristic of cancer), increased frailty according to the CSHA Frailty Index, Thromboembolic complications, gastrointestinal complications, cardiac complications, neurologic complications, metabolic complications (these elements are claimed in the alternative and do not need to be mapped).
As to claim 44, Arvey teaches the method according to claim 42, wherein the decrease in organ function is a function of the age of the human subject (Arvey Para [0006]: the invention is predictive of age-effects from immunological changes, by computing “immune age”).
As to claim 45, Arvey teaches the method according to claim 43, wherein the risk of medical complications is a function of the age of the human subject (Arvey Para [0006]: the invention is predictive of age-effects from immunological changes, by computing “immune age”).
As to claim 46, Arvey teaches the method according to claim 42, wherein the prospective decrease in organ function is causally linked to inflammatory disease, degenerative syndromes, malignant tumors, or viral infections of the human subject (Arvey Para [0005]: the condition is linked to inflammatory disease).
As to claim 47, Arvey teaches the method according to claim 43, wherein the risk of medical complications is causally linked to inflammatory disease (Arvey Para [0005]: the condition is linked to inflammatory disease), degenerative syndromes (this element is recited in the alternative and does not need to be mapped), malignant tumors (Arvey para [0089]: a decrease in lung, renal, or heart function characteristic of cancer), or viral infections of the human subject (this element is recited in the alternative and does not need to be mapped).
As to claim 48, Arvey teaches the method according to claim 47, wherein the inflammatory disease is an acute inflammatory disease, or a chronic inflammatory disease (Arvey Para [0005]: the condition is linked to inflammatory disease, which is inherently either acute or chronic).
As to claim 49, Arvey teaches the method according to claim 47, wherein the acute inflammatory disease is caused by an allergic reaction, frostbite, chemical irritants, infection (Arvey Para [0167]: latent infection re-activation), burn, trauma, cuts, or laceration (these elements are claimed in the alternative and do not all need to be mapped).
As to claim 50, Arvey teaches the method according to claim 47, wherein the chronic inflammatory disease is cardiovascular disease (these elements are claimed in the alternative and do not all need to be mapped), rheumatoid arthritis (Arvey Para [0162]: rheumatoid arthritis), autoimmune disease, neurological disease (these elements are claimed in the alternative and do not all need to be mapped), or cancer (Arvey para [0089]: a decrease in lung, renal, or heart function characteristic of cancer).
As to claim 51, Arvey teaches the method according to claim 47 (see the rejection to claim 47, which is fully applicable to this claim), wherein the degenerative syndrome is selected from the group comprising Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, multiple sclerosis, Parkinson's disease, Spinal muscular atrophy, prion disease, Pick's disease (these elements limit the element of “degenerative syndromes” in claim 47. However, in claim 47, “degenerative syndromes” are one of many possible elements recited in the alternative as a set; since “degenerative syndromes” did not need to be mapped in claim 47 to reject claim 47, the particular limitations presented in claim 51 do not need to be mapped to reject dependent claim 51).
As to claim 52, Arvey teaches the method according to claim 47, wherein the malignant tumor is a malignant tumor of connective tissue (Arvey Para [0089]: gastrointestinal stromal tumor), endothelium (Arvey Para [0089]: Kaposi sarcoma) and mesothelium (Arvey Para [0089]: mesothelioma), blood (Arvey Para [0089]: leukemia), lymphoid cells (Arvey Para [0089]: lymphoma), muscle, epithelial tissues (Arvey Para [0089]: ovarian epithelial cancer), neural tissue (Arvey Para [0089]: neuroectodermal tumors).
As to claim 53, Arvey teaches the method according to claim 47 (see the rejection to claim 47, which is fully applicable to this claim), wherein the viral infection is caused by a virus selected from the group viral families comprising herpesviridae, papovaviridae, arenaviridae, astroviridae, bunyaviridae, coronaviridae, flaviviridae, orthomyxoviridae, paramyxoviridae, picornaviridae, reoviridae, retroviridae, rhabdoviridae, togaviridae (these elements limit the element of “viral infection” in claim 47. However, in claim 47, “viral infection” are one of many possible elements recited in the alternative as a set; since “viral infection” did not need to be mapped in claim 47 to reject claim 47, the particular limitations presented in claim 53 do not need to be mapped to reject dependent claim 53).
As to claim 54, Arvey teaches the method according to claim 35, wherein one or more devices are used to perform point-of-care testing (POCT devices) to determine at least the concentration of salivary neutrophils and/or salivary IL-6 (Arvey Para [0003]: the assays listed include at least one that has the property that it can be performed in a point-of-care setting, such as bead assays, aptamer assays, ELISA assays, and ELISPOT).
As to claim 55, Arvey teaches the method according to claim 54, wherein the one or more POCT devices used comprise one or more microfluidic biochip platforms to detect and quantify salivary IL-6 concentration and/or the salivary neutrophil concentration (Arvey Para [0030]: probes on a wafer chip).
As to claim 57, Arvey teaches a method of treating a human subject (Arvey Abstract: predicting immune health) characterized by predictive score S P>0 (Arvey Para [0143]: the predictive index score may be calculated by combining scores from distinct aspects of immune health) indicating that the human subject has an increased risk of an adverse clinical and/or treatment outcome (Arvey Abstract: predicting immune health), wherein predictive score is calculated using a Theta Heaviside function using at least a normalized salivary IL-6 value (Ñ IL-6) and a normalized salivary neutrophil value (Ñ NP) (Arvey Para [0043]: values compared to reference exaptation values for the immune index calculation), wherein the normalized salivary IL-6 value (Ñ IL-6) and normalized salivary value (Ñ NP) are determined according to a scoring algorithm (Arvey Figure 14B: the scores are kept positive in an index, which is the functional purpose of using the step function that is the Thea Heaviside function to avoid negative values as components of the sum calculation), comprising the steps of
a) assigning a predictive IL-6 score Ñ IL-6=0, if the salivary IL-6 concentration is lower than or equal to the normalization value of IL-6 (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference; the claimed limitation is at once envisaged from these three possibilities),
b) calculating Ñ IL-6 as the ratio of salivary IL-6 concentration:IL-6 normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ IL-6, for a salivary IL-6 concentration which is greater than the IL-6 normalization value (Arvey Para [0055]: normalizing a biomarker value against an expected reference value),
c) assigning a predictive neutrophil (NP) score Ñ NP=0, if the salivary neutrophil concentration is lower than or equal to the normalization value for salivary neutrophils (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference; the claimed limitation is at once envisaged from these three possibilities),
d) calculating Ñ NP as the ratio of salivary neutrophil concentration: salivary neutrophil normalization value and wherein the numerical value of 1 is subtracted from the normalization result yielding Ñ NP, for a salivary neutrophil concentration which is greater than the IL-6 normalization value (Arvey Para [0006]: determining if a particular value is less than, the same, or greater than a reference), and wherein the predictive score (S P) is calculated as S P=Ñ NP+Ñ IL-6 (Arvey Para [0143]: the predictive index score may be calculated by combining scores from distinct aspects of immune health).
As to claim 58, Arvey teaches the method of treating a human subject according to claim 57, wherein the treatment is a precautionary treatment prior to the worsening of the medical condition, or wherein the treatment is chosen to treat the first clinical manifestations of an increasing disease severity or activity (Arvey Abstract: predicting immune health).
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 to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 36-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20210247403 A1 (“Arvey”) in view of Applicant’s Admitted Prior Art at page 11. See page 11 lines 1-6 of the instant Application’s Specification for a discussion of prior art that is by different inventive entities from the inventor of the instant application and admitted to be published in respective years that are more than one year before the effective filing date of the instant application.
See MPEP § 21219 (I) and (II) regarding the legal standard for “Admissions as Prior Art”.
As to claim 36, Arvey teaches the method according to claim 35 (see the rejection of claim 35), but does not teach:
wherein the salivary normalization value for IL-6 is 10 pg/ml and wherein the salivary normalization value for neutrophils is 90 cells/μl.
Nevertheless, Applicant’s Admitted Prior Art teaches wherein the salivary normalization value for IL-6 is 10 pg/ml and wherein the salivary normalization value for neutrophils is 90 cells/μl (see the admission of work by another on page 11 lines 1-6 of the Specification of the instant application).
Arvey and Applicant’s Admitted Prior Art are in the same field of diagnostics. Furthermore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Arvey to include the teachings of Applicant’s Admitted Prior Art because exceeding a “normal” amount would be a quantitative indicator of an abnormality. There would be a reasonable expectation of success because insertion of a reasonable quantity as a constant in the claimed formula would lead to the desired computation using standard mathematics and arithmetic.
As to claim 37, Arvey in view of Applicant’s Admitted Prior Art teaches the method according to claim 36, wherein a predictive score (S P) of S P=0 indicates a low risk of an adverse clinical and/or treatment outcome and a predictive score S P>0 indicates an increased risk of an adverse clinical and/or treatment outcome (Arvey Abstract: predicting immune health).
As to claim 38, Arvey in view of Applicant’s Admitted Prior Art teaches the method according to claim 36, wherein the clinical and/or treatment outcome between two or more human subjects at risk of prospective clinical condition is determined, wherein the method comprises calculating a predictive score S P for each human subject, wherein the subject with the lowest predictive score has the lowest risk of an adverse clinical and/or treatment outcome (Arvey Abstract: predicting immune health).
Claim(s) 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20210247403 A1 (“Arvey”) in view of Applicant’s Admitted Prior Art pages at 15-16. See page 15 lines 24 to page 16 line 4 of the instant Application’s Specification for a discussion of prior art that is by different inventive entities from the inventor of the instant application and admitted to be published in respective years that are more than one year before the effective filing date of the instant application.
See MPEP § 21219 (I) and (II) regarding the legal standard for “Admissions as Prior Art”.
As to claim 41, Arvey teaches the method according to claim 40 (see the rejection of claim 40), wherein the normalization values for said one or more biomarkers are
interleukin receptor antagonist: 2810 pg/ml,
interleukin-1 beta: 128 pg/ml,
interleukin-7: 8.29 pg/ml,
interleukin-8: 323 pg/ml,
interleukin-10: 3.26 pg/ml,
interleukin-13: 0.70 pg/ml,
colony stimulating factor 3: 23.3 pg/ml,
C-X-C motif chemokine ligand 10 (CXCL10): 949 pg/ml,
C-C motif chemokine ligand 3 (CCL3): 2.28 pg/ml,
C-C motif chemokine ligand 11 (CCL11): 5.33 pg/ml,
interferon-gamma: 28.8 pg/ml,
tumor necrosis factor-alpha: 12.5 pg/ml,
total alpha-synuclein: 314 pg/ml,
amyloid beta 1-42: 21.1 pg/ml,
protein t-TAU: 9.6 pg/ml,
CA125: 384 units/ml,
TPS: 110 units/ml,
CA19-9: 27.1 units/ml,
CEA: 197.6 ng/ml,
SCC 140 ng/ml
(see the admission of work by another on page 15 lines 24 to page 16 line 4 of the Specification of the instant application).
Arvey and Applicant’s Admitted Prior Art at pages 15-16 are in the same field of diagnostics. Furthermore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Arvey to include the teachings of Applicant’s Admitted Prior Art because exceeding a “normal” amount would be a quantitative indicator of an abnormality. There would be a reasonable expectation of success because insertion of a reasonable quantity as a constant in the claimed formula would lead to the desired computation using standard mathematics and arithmetic.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20210247403 A1 (“Arvey”) in view of US 20120329070 A1 ("Blakely").
As to claim 56, Arvey teaches the method according to claim 54 (see the rejection of claim 54), but does not teach wherein the POCT device is a lateral flow device, wherein the lateral flow device comprises at least two lateral flow strips for the quantification of IL-6 and a second biomarker selected from the group comprising interleukin receptor antagonist, interleukin-1 beta, interleukin-7, interleukin-8, interleukin-10, interleukin-13, colony stimulating factor 3, C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 3 (CCL3), C-C motif chemokine ligand 11 (CCL11), interferon-gamma, tumor necrosis factor-alpha, total alpha-synuclein, amyloid beta 1-42, protein t-TAU, CA125, TPS, CA19-9, CEA, SCC, or leukocyte esterase.
Nevertheless, Blakely teaches:
wherein the POCT device is a lateral flow device (Blakely Para [0072]: lateral flow device), wherein the lateral flow device comprises at least two lateral flow strips for the quantification of IL-6 (Blakely Para [0072]: lateral flow device detects IL-6) and a second biomarker selected from the group comprising interleukin receptor antagonist, interleukin-1 beta, interleukin-7, interleukin-8, interleukin-10, interleukin-13, colony stimulating factor 3, C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 3 (CCL3), C-C motif chemokine ligand 11 (CCL11), interferon-gamma, tumor necrosis factor-alpha (Blakely Para [0012]: TNFalpha can be measured in the invention), total alpha-synuclein, amyloid beta 1-42, protein t-TAU, CA125, TPS, CA19-9, CEA, SCC, or leukocyte esterase (these elements are claimed in the alternative and do not need to all be mapped).
Arvey and Blakely are in the same field of diagnostics. Furthermore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Arvey to include the teachings of Blakely because lateral flow assays can be used in a variety of settings, and TNFalpha combined with IL-6 helps to inform the type of immune activity indicates by the saliva concentrations of the two markers in combination. There would be a reasonable expectation of success because lateral flow assays are a standard and commercialized way to perform point-of-care assays. Note that Blakely also teaches the use detection of neutrophil levels, emphasizing additional overlap between the steps of Avery and the steps of Blakely.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Panneer Selvam, Niranzena, and Jayachandran Sadaksharam. "Salivary interleukin‐6 in the detection of oral cancer and precancer." Asia‐Pacific Journal of Clinical Oncology 11.3 (2015): 236-241.
Domnich, Maksim, et al. "Oral neutrophils: underestimated players in oral cancer." Frontiers in immunology 11 (2020): 565683.
Sahibzada, Haafsa Arshad, et al. "Salivary IL-8, IL-6 and TNF-α as potential diagnostic biomarkers for oral cancer." Diagnostics 7.2 (2017): 21.
Koizumi, Tomonobu, Vivek Shetty, and Masaki Yamaguchi. "Salivary cytokine panel indicative of non-small cell lung cancer." Journal of International Medical Research 46.9 (2018): 3570-3582.
US 20220165372 A1: see claim 18
US 20200148760 A1: see title; see paragraphs 131-132 regarding baseline quantities
US 20100179072 A1: The claims recite saliva and neutrophil measurement; the specification recites IL-6 as part of a list; paragraph [0103] describes quantities relative to historical normal values; paragraph [0088] describes positive changes only, not negative changes, which addresses some of the characteristics of the Theta Heaviside function in the Applicant’s independent claims of the instant application.
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/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 September 21, 2026
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