DETAILED ACTION
In application filed on 05/02/2023, Claims 1, 2, 4-10,11, 12-16, 23, 33-35 and 87-88 are pending. The claim set submitted on 12/08/2025 is considered because this is the most recent claim set with some preliminary amendments. Claims 1, 4-10, 12-16, 23, 33-35 and 87-88 are considered in the current office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/02/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 12/08/2025 is acknowledged. Claims 2 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/08/2025.
Group I, Claims 1, 4-10, 12-16, 23, 33-35 and 87-88 are considered on the merits below.
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 1, 4-10, 12-16, 23, 33-35 and 87-88 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation. All claims are directed to statutory categories, i.e., a method (Claims 1, 4-10, 12-16, 23, 33-35 and 87-88) (Step 1: YES).
Analysis:
Claim 1: Ineligible.
Step 1:
The claim recites a series of steps or acts, including “treating a subject to reduce risk of mortality of the subject”. Thus, the claim is directed to a method, which is one of the statutory categories of invention (Step 1: YES).
Step 2A Prong 1:
Claim 1 recites “comparing the measured level of each protein to a reference level for each measured level of protein, wherein each of the two proteins (math or mental step)”. Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 1 relates to using a math or mental process to “compare the measured level of each protein to a reference level for each measured level of protein, wherein each of the two proteins”.
Also, it appears the claim that recites a natural correlation/law of nature (Step 2A, Prong 1: Patent Ineligible).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the comparison is done, the step of “administering to the subject an effective dose of a therapeutic treatment to decrease the risk of mortality of the subject…” is performed. This administering step appears to be merely “applying” the abstract idea and the natural correlation. MPEP 2106.05.
Also the step of “measuring the level of each of two proteins in a biological sample from the subject” is recited at a high level of generality that it amounts to mere data gathering (insignificant extra-solution activity). See MPEP 2106.05(g) (Step 2A, Prong 2: NO).
Step 2B:
Furthermore, the courts have found that limitations adding insignificant extrasolution activity to the judicial exception, such as mere data gathering in conjunction with a law of nature or abstract idea, are limitations found not to be enough to qualify as ‘significantly more’ when recited in a claim with a judicial exception (see the 2014 Interim Guidance on Patent Subject Matter Eligibility of the Federal Register dated December 16, 2014; and MPEP 2106.05(I)(A)). Note that mere data gathering is not significantly more than the abstract idea. See MPEP 2106.05(g).
Here, there are no additional elements which are significantly more than the abstract idea.The steps of “measuring the level of each of two proteins in a biological sample from the subject” appears to be well-understood, routine, and conventional (WURC) in the field of clinical diagnostics, as evidenced by Gyllensten et al. (WO2015193427A1) in view of Shen et al. (US20170306031A1). (Step 2B: NO).
Therefore, Claim 1 is ineligible.
Moreover, Claims 4-10, 12-16, 23, 33-35 and 87-88 are rejected by virtue of their dependency on Claim 1.
Claims 4-10, 12-16, 23 and 33-35: Ineligible.
Step 2A, Prong One and Prong Two: Claims 8-10 further define the data gathering steps including the proteins measured, which appear to be generic and WURC.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claims 4-10, 12-16, 23 and 33-35 are ineligible.
Claim 87: Ineligible.
Step 1:
The claim recites a series of steps or acts, including “determining the efficacy of the therapeutic treatment in the subject”. Thus, the claim is directed to a method, which is one of the statutory categories of invention (Step 1: YES).
Step 2A Prong 1:
Claim 87 recites “determining that the treatment is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15… (math or mental step)”. Therefore, the claim is directed towards an abstract idea, and more specifically to the abstract idea group of a math or mental process since claim 87 relates to using a math or mental process to “determine that the treatment is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15…”.
Also, it appears the claim that recites a natural correlation/law of nature (Step 2A, Prong 1: Patent Ineligible).
Step 2A, Prong 2:
This judicial exception is not integrated into a practical application.
Once the determining is done, no further action takes place.
Also the step of “measuring the level of each of two proteins in a biological sample from the subject after administering the treatment” is recited at a high level of generality that it amounts to mere data gathering (insignificant extra-solution activity). See MPEP 2106.05(g) (Step 2A, Prong 2: NO).
Step 2B:
Furthermore, the courts have found that limitations adding insignificant extrasolution activity to the judicial exception, such as mere data gathering in conjunction with a law of nature or abstract idea, are limitations found not to be enough to qualify as ‘significantly more’ when recited in a claim with a judicial exception (see the 2014 Interim Guidance on Patent Subject Matter Eligibility of the Federal Register dated December 16, 2014; and MPEP 2106.05(I)(A)). Note that mere data gathering is not significantly more than the abstract idea. See MPEP 2106.05(g).
Here, there are no additional elements which are significantly more than the abstract idea. The steps of “measuring the level of each of two proteins in a biological sample from the subject after administering the treatment” appears to be well-understood, routine, and conventional (WURC) in the field of clinical diagnostics, as evidenced by Gyllensten et al. (WO2015193427A1) in view of Shen et al. (US20170306031A1) as applied to claim 1 above, and further in view of Buendgens et al. ("Growth differentiation factor‐15 is a predictor of mortality in critically ill patients with sepsis." Disease markers 2017.1 (2017): 5271203) (Step 2B: NO).
Therefore, Claim 87 is ineligible.
Moreover, Claim 88 is rejected by virtue of their dependency on Claim 87.
Claim 88 is: Ineligible.
Step 2A, Prong One and Prong Two: Claim 88 further define the abstract idea, which appear to be generic and WURC.
Step 2B: The claims do not recite any elements which are significantly more.
Therefore, Claim 88 is ineligible.
Claim Rejections - 35 USC § 103
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 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-10, 12-16, 23 and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over by Gyllensten et al. (WO2015193427A1) in view of Shen et al. (US20170306031A1).
Regarding Claim 1, Gyllensten teaches a method of treating a subject to reduce risk of mortality of the subject (See Abstract… determining an individualized normal level of a biomarker for a test subject for use in analysis of said biomarker in the diagnosis or monitoring of a disease or its treatment in said subject, thereby teaching “reduce risk of mortality for a test subject”), the method comprising:
Measuring the level (See Page 18, line 5… determine the abundance level of a biomarker in a sample) of each of two proteins (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays) in a biological sample from the subject (See Page 18, lines 7-8… thereby to quantify the biomarker in the sample; See Page 15, lines 15… a biomarker may be detected in more than one type of clinical sample from a subject; lines 21-22… The abundance level is simply a measure or indication of the level or amount of a biomarker in a given clinical sample);
comparing the measured level of each protein (See Page 6, lines 35-36-Page 7, lines 1-4… an adjusted value for the abundance level of said biomarker in a said sample) to a reference level for each measured level of protein (Page 7, lines 3-4… to an adjusted value for the abundance level of said biomarker in a sample from a subject free from said disease) (See Page 7… comparing the adjusted value from (b) to an adjusted value for the abundance level of said biomarker in a sample from a subject free from said disease), wherein each of the two proteins (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays) is:
(a) growth/differentiation factor 15 (GDF15);…d) WAP four-disulfide core domain protein 2 (WFDC2) (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays); and
(i) the measured level of GDF15, …, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is increased relative to the reference level (See Page 144, lines 31-32…GDF-15 also showed higher levels in cases compared to controls.)
Also, Examiner submits that the limitation “and/or;(ii) the measured level of ANTRX2, HPGDS, ADAM22, GHR, or CILP2 is decreased relative to the reference level” in viewed as an alternative (optional) limitation, thus not required by the Claim.
Gyllensten does not explicitly teach:
“administering to the subject an effective dose of a therapeutic treatment to decrease the risk of mortality of the subject if (i) the measured level of GDF15, …, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is increased relative to the reference level”.
In the analogous art of binding proteins, such as antibodies, that bind to a GDNF Family Receptor Alpha Like (GFRAL) protein, including human GFRAL protein, and methods of their use, Shen teaches:
administering to the subject an effective dose (See Para 0410… administering to an individual an effective amount of an anti-GFRAL antibody or fragment thereof) of a therapeutic treatment to decrease the risk of mortality of the subject (See Para 0406… a method to treat a subject suffering from cachexia; See Para 0247… Cachexia can greatly contribute to morbidity of patients suffering from some chronic diseases (e.g., cancer,…cachexia is common (occurring in most terminally ill cancer patients), and is responsible for about a quarter of all cancer-related deaths, thereby teaching “decrease the risk of mortality of the subject”) (See Para 0409… Administering the subject an anti-GFRAL antibody or fragment thereof to such a subject can decrease or prevent one or more of the symptoms associated with a GDF15-mediated disease, disorder or condition. For example, administering an anti-GFRAL antibody or fragment thereof of the present disclosure can increase body weight and/or appetite in a subject. As another example, administering an anti-GFRAL antibody or fragment thereof of the present disclosure can maintain body weight in a subject or reduce body weight loss is a subject.) if (i) the measured level of GDF15, …, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is increased relative to the reference level (See Para 0406… Such subjects include subjects who have elevated levels of GDF15…See Para 0407… also disclosed is a method for modulating GDF15 activity in a patient having elevated GDF15 activity. As used herein, “elevated GDF15 activity” refers to increased activity or amount of GDF15 in a biological fluid of a subject in comparison to a normal subject).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gyllensten to incorporate ““administering to the subject an effective dose of a therapeutic treatment to decrease the risk of mortality of the subject if (i) the measured level of GDF15, …, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is increased relative to the reference level”, as taught by Shen for the benefit of decreasing or preventing one or more of the symptoms associated with a GDF15-mediated disease, disorder or condition. For example, administering an anti-GFRAL antibody or fragment thereof of the present disclosure can increase body weight and/or appetite in a subject (Shen, Para 0410), allowing for the provision of therapeutic agents effective to treat weight loss associated with a number of diseases and conditions, including wasting diseases such as cachexia or sarcopenia and inflammatory conditions such as systemic inflammation or an acute inflammatory response, cancer, chronic renal disease, chronic obstructive pulmonary disease, AIDS, tuberculosis, chronic inflammatory disease, systemic inflammation, and muscle wasting diseases, including in which involuntary body weight loss and/or muscle mass loss is involved (Shen Para 0005).
Regarding Claim 4, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2). (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Examiner submits that the claimed “or (e) anthrax toxin receptor 2 (ANTRX2)” is viewed as optional and thus not required by the Claim.
Regarding Claim 5, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 6, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 7, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 8, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 9, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 10, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…
(d) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 12, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
growth/differentiation factor 15 (GDF15); (b) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 13, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15); (b) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 14, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches wherein the each of two proteins is:
(a) growth/differentiation factor 15 (GDF15);…(c) WAP four-disulfide core domain protein 2 (WFDC2)… (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays).
Regarding Claim 15, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten does not teach that the therapeutic treatment is any one or more of Aimovig TM (erenumab-aooe; AMG 334), Aranesp@ (darbepoetin alfa), AVSOLATM (infliximab-axxq), BLINCYTO@ (blinatumomab), Corlanor@ (ivabradine), Enbrel@ (etanercept), EPOGEN® (epoetin alfa), EVENITYTM (romosozumab- aqqg), IMLYGIC@ (talimogene laherparepvec), KanjintiTM (trastuzumab-anns), Kyprolis® (carfilzomib), MVASITM (bevacizumab-awwb), Neulasta® (pegfilgrastim), NEUPOGEN® (filgrastim), Nplate@ (romiplostim), Otezla® (apremilast), ParsabivTM (etelcalcetide), Prolia® (denosumab), Repatha® (evolocumab), Sensipar@ (cinacalcet), Vectibix® (panitumumab), or XGEVA® (denosumab).
In the analogous art of binding proteins, such as antibodies, that bind to a GDNF Family Receptor Alpha Like (GFRAL) protein, including human GFRAL protein, and methods of their use, Shen teaches that the therapeutic treatment (See Para 0430… Suitable inhibitors of TNFα include for example,…infliximab (Remicade®, Janssen Biotech)) is any one or more of Aimovig TM (erenumab-aooe; AMG 334), Aranesp@ (darbepoetin alfa), AVSOLATM (infliximab-axxq), BLINCYTO@ (blinatumomab), Corlanor@ (ivabradine), Enbrel@ (etanercept), EPOGEN® (epoetin alfa), EVENITYTM (romosozumab- aqqg), IMLYGIC@ (talimogene laherparepvec), KanjintiTM (trastuzumab-anns), Kyprolis® (carfilzomib), MVASITM (bevacizumab-awwb), Neulasta® (pegfilgrastim), NEUPOGEN® (filgrastim), Nplate@ (romiplostim), Otezla® (apremilast), ParsabivTM (etelcalcetide), Prolia® (denosumab), Repatha® (evolocumab), Sensipar@ (cinacalcet), Vectibix® (panitumumab), or XGEVA® (denosumab) (See Para 0430… infliximab (Remicade®, Janssen Biotech); thereby teaching “AVSOLATM (infliximab-axxq)”. Under BRI, it is known that Avsola (infliximab-axxq) is a biosimilar to Remicade (infliximab).).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gyllensten to incorporate that the therapeutic treatment is any one or more of Aimovig TM (erenumab-aooe; AMG 334), Aranesp@ (darbepoetin alfa), AVSOLATM (infliximab-axxq), BLINCYTO@ (blinatumomab), Corlanor@ (ivabradine), Enbrel@ (etanercept), EPOGEN® (epoetin alfa), EVENITYTM (romosozumab- aqqg), IMLYGIC@ (talimogene laherparepvec), KanjintiTM (trastuzumab-anns), Kyprolis® (carfilzomib), MVASITM (bevacizumab-awwb), Neulasta® (pegfilgrastim), NEUPOGEN® (filgrastim), Nplate@ (romiplostim), Otezla® (apremilast), ParsabivTM (etelcalcetide), Prolia® (denosumab), Repatha® (evolocumab), Sensipar@ (cinacalcet), Vectibix® (panitumumab), or XGEVA® (denosumab)”, as taught by Shen for the benefit of providing therapy involving TNFα and IL-1 which are cytokines known to be involved in mediation of the proinflammatory response, which are also implicated in muscle depletion, anorexia and cachexia (Shen, Para 0429) allowing for the provision of therapeutic agents effective to treat weight loss associated with a number of diseases and conditions, including wasting diseases such as cachexia or sarcopenia and inflammatory conditions such as systemic inflammation or an acute inflammatory response, cancer, chronic renal disease, chronic obstructive pulmonary disease, AIDS, tuberculosis, chronic inflammatory disease, systemic inflammation, and muscle wasting diseases, including in which involuntary body weight loss and/or muscle mass loss is involved (Shen Para 0005).
Regarding Claim 16, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten does not teach that the therapeutic treatment is a biological or a pharmaceutical drug that (a) reduces the risk of mortality from a neoplastic disease or disorder;(b) reduces the risk of mortality from a nervous disease or disorder;(c) reduces the risk of mortality from a circulatory disease or disorder;(d) reduces the risk of mortality from a respiratory disease or disorder;(e) reduces the risk of mortality from inflammation or an inflammatory disease or disorder; and/or (f) reduces the risk of mortality from an autoimmune disease or disorder.
In the analogous art of binding proteins, such as antibodies, that bind to a GDNF Family Receptor Alpha Like (GFRAL) protein, including human GFRAL protein, and methods of their use, Shen teaches that the therapeutic treatment is a biological or a pharmaceutical drug (See Para 0430… Suitable inhibitors of TNFα include for example, etanercept (Enbrel®, Pfizer/Amgen), infliximab (Remicade®, Janssen Biotech)) that (a) reduces the risk of mortality from a neoplastic disease or disorder;(b) reduces the risk of mortality from a nervous disease or disorder;(c) reduces the risk of mortality from a circulatory disease or disorder;(d) reduces the risk of mortality from a respiratory disease or disorder;(e) reduces the risk of mortality from inflammation or an inflammatory disease or disorder; (Examiner interprets limitations (a)- (e) as optional limitations, therefore not required by the claim) and/or (f) reduces the risk of mortality See Para 0406… a method to treat a subject suffering from cachexia; See Para 0247… Cachexia can greatly contribute to morbidity of patients suffering from some chronic diseases (e.g., cancer,…cachexia is common (occurring in most terminally ill cancer patients), and is responsible for about a quarter of all cancer-related deaths, thereby teaching “reduces the risk of mortality”) from an autoimmune disease or disorder (See Para 0429…Thus, TNFα inhibitors and IL-1 inhibitors that are used in the treatment of rheumatoid arthritis may also be useful in the treatment of cachexia; See Para 0407…autoimmune diseases such as, arthritis and inflammation…).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gyllensten to incorporate that the therapeutic treatment is a biological or a pharmaceutical drug that (a) reduces the risk of mortality from a neoplastic disease or disorder;(b) reduces the risk of mortality from a nervous disease or disorder;(c) reduces the risk of mortality from a circulatory disease or disorder;(d) reduces the risk of mortality from a respiratory disease or disorder;(e) reduces the risk of mortality from inflammation or an inflammatory disease or disorder; and/or (f) reduces the risk of mortality from an autoimmune disease or disorder, as taught by Shen for the benefit of providing therapy involving TNFα and IL-1 which are cytokines known to be involved in mediation of the proinflammatory response, which are also implicated in muscle depletion, anorexia and cachexia (Shen, Para 0429) and also for the treatment of rheumatoid arthritis may be administered locally and directly to the tumor site (Shen, Para 0430), allowing for the provision of therapeutic agents effective to treat weight loss associated with a number of diseases and conditions, including wasting diseases such as cachexia or sarcopenia and inflammatory conditions such as systemic inflammation or an acute inflammatory response, cancer, chronic renal disease, chronic obstructive pulmonary disease, AIDS, tuberculosis, chronic inflammatory disease, systemic inflammation, and muscle wasting diseases, including in which involuntary body weight loss and/or muscle mass loss is involved (Shen Para 0005).
Regarding Claim 23, the method of claim 16 is obvious over Gyllensten in view of Shen.
Examiner submits that the limitation “…circulatory disease or disorder” is viewed as an optional limitation and thus not required by Claim 16.
However, for the purpose of compact prosecution, Examiner submits that Gyllensten further teaches that the circulatory disease or disorder (See Page 14, line 9…stroke (e.g. ischemic stroke; See Page 46, line 11…stroke) is hypercholesterolemia, myocardial infarction, and/or stroke (See Page 14, line 9…stroke (e.g. ischemic stroke; See Page 46, line 11…stroke).
Regarding Claim 33, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten further teaches the reference level (Page 7, lines 3-4… to an adjusted value for the abundance level of said biomarker in a sample from a subject free from said disease) is a mean level of the biomarker in a biological sample from a population of subjects determined to be healthy (See Abstract…the level of a biomarker in samples of a body fluid or tissue in a control population free from said disease, to obtain a set of control abundance levels for said biomarker in a said sample) or not to be at an increased risk of mortality (This limitation is viewed as optional).
Regarding Claim 34, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches measuring the level (See Page 18, line 5… determine the abundance level of a biomarker in a sample) of each of at least three (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays; See Page 67; Page 69, Table 9…Spondin-1 (SPON1), GDF-15, thereby teaching “at least 3”), at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 proteins in the biological sample from the subject (See Page 18, lines 7-8… thereby to quantify the biomarker in the sample; See Page 15, lines 15… a biomarker may be detected in more than one type of clinical sample from a subject; lines 21-22… The abundance level is simply a measure or indication of the level or amount of a biomarker in a given clinical sample).
Regarding Claim 35, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten teaches that the biological sample (See Page 15, lines 15… a biomarker may be detected in more than one type of clinical sample) is a blood sample (See Page 1, lines 26-27…biomarkers used for disease diagnosis or monitoring should ideally be uniquely present or overexpressed in the diseased tissue or blood).
Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Gyllensten et al. (WO2015193427A1) in view of Shen et al. (US20170306031A1) as applied to claim 1 above, and further in view of Buendgens et al. ("Growth differentiation factor‐15 is a predictor of mortality in critically ill patients with sepsis." Disease markers 2017.1 (2017): 5271203).
Regarding Claim 87, the method of claim 1 is obvious over Gyllensten in view of Shen.
Gyllensten further teaches determining the efficacy of the therapeutic treatment in the subject (See Page 14, lines 24-32…diagnosis or monitoring of a disease and/or its treatment. …Thus diagnosis may include identifying the disease in a subject. A biomarker may also be used in prognosis, for example to predict the progress or development of a disease, or to predict it's response to treatment e.g. to a given therapy, for example to determine which therapeutic intervention (e.g. of a number of possible options) may be effective, or may work best (or be expected to work best) or be most appropriate. Responsiveness to treatment may also be monitored) comprising:
measuring the level (See Page 18, line 5… determine the abundance level of a biomarker in a sample) of each of two proteins (See page 54, Table 4 for the biomarkers including proteins GDF-15 and WFDC2, quantified by PEA Assays) in a biological sample from the subject (See Page 18, lines 7-8… thereby to quantify the biomarker in the sample; See Page 15, lines 15… a biomarker may be detected in more than one type of clinical sample from a subject; lines 21-22… The abundance level is simply a measure or indication of the level or amount of a biomarker in a given clinical sample); after administering the treatment (See Page …biomarker may also be used in prognosis, for example to predict the progress or development of a disease, or to predict it's response to treatment e.g. to a given therapy, thereby teaching “after administering the treatment”); and
determining that the treatment is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15, TSP-2, RBL2, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 (See Page 6, lines 35-36-Page 7, lines 1-4… an adjusted value for the abundance level of said biomarker in a said sample; See Page 50 table for GDF-15) is decreased relative to the reference level or to the level in the sample from the subject before treatment (See Page 6, line 16-19…comparing the adjusted value(s) of the abundance level of the candidate or putative biomarker derived from a subject (or population of subjects) with a disease to the adjusted value(s) of the abundance level of the candidate or putative biomarker derived from a subject (or population of subjects) free from the disease, i.e. a control subject or population. A difference between the adjusted levels (i.e. an increase or decrease).
The claimed “and/or (ii) the measured level of ANTRX2, HPGDS, ADAM22, GHR, or CILP2 is increased relative to the reference level or to the level in the sample from the subject before treatment” is viewed as an optional limitation and thus not required by the claim.
Gyllensten does not explicitly teach:
“determining that the treatment is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15, TSP-2, RBL2, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is decreased relative to the reference level or to the level in the sample from the subject before treatment”.
In the analogous art of growth differentiation factor-15 being a predictor of mortality in critically Ill patients with sepsis, Buendgens teaches:
“determining that the treatment (‘ICU treatment ‘) is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15, TSP-2, RBL2, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is decreased relative to the reference level (See Page 4, Section 3.3…Strikingly, patients that survived ICU treatment showed significant lower serum levels of GDF-15 than nonsurvivors (median 5028 versus 9505 pg/mL; p < 0.001; Figure 3(a)) in all patients as well as in the subgroup of sepsis patients (median 6244 pg/mL versus 9964 pg/mL; p = 0.01; Figure 3(b))).
Examiner further submits that the limitation “or to the level in the sample from the subject before treatment” is viewed as optional and thus not required by the claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gyllensten and Shen to incorporate “determining that the treatment is effective in reducing risk of mortality of the subject if (i) the measured level of GDF15, TSP-2, RBL2, WFDC2, SERPINA3,SPON1, SPON2, SAA1, SAA2, C5Aat, TNFRSF1A, ANG2, MMP12, TAGLN,SVEP1, IGFPB2, NTproBNP, TMED10, RNase1, cTnT, ROR2, beta-2-M, IGFPB6,tetranectin, DCTPP1, EDAR, EPO, C7, CD62L, UNC5B, brorin, EGFR, SPINK5,IGSF3, FCRL1, PTN, RGMB, EPHB2, TREM-1, elafin, or WISP-2 is decreased relative to the reference level or to the level in the sample from the subject before treatment”, as taught by Buendgens for the benefit of disclosing that patients that survived ICU treatment showed significant lower serum levels of GDF-15 than nonsurvivors (Buendgens, See Page 4, Section 3.3), which suggests that High GDF-15 levels after ICU treatment predict short- and long-term mortality risk (Buendgens, Abstract).
Claim 88 is rejected under 35 U.S.C. 103 as being unpatentable over Gyllensten et al. (WO2015193427A1) in view of Shen et al. (US20170306031A1) further in view of Buendgens et al. ("Growth differentiation factor‐15 is a predictor of mortality in critically ill patients with sepsis." Disease markers 2017.1 (2017): 5271203) as applied to claim 87 above, and further in view of Prescott et al. (US20170100460A1).
Regarding Claim 88, the method of claim 87 is obvious over Gyllensten in view of Shen and further in view of Buendgens.
The combination of Gyllensten, Shen and Buendgen does not teach continuing the therapeutic treatment if the treatment is determined effective in reducing risk of mortality.
In the analogous art of the field of therapeutic intervention in cardiovascular disease. More particularly, it relates to growth differentiation factor 15, a pro-inflammatory peptide. It further relates to serelaxin, a hormone recently shown to be effective in treating heart failure, Prescott teaches continuing (‘and one or more optional repeat treatments as needed’) the therapeutic treatment (See Para 0055… Depending on the subject, the serelaxin administration is maintained for as specific period of time or for as long as needed to achieve stability in the subject. For example, the duration of serelaxin treatment is preferably kept at a range of about 4 hours to about 96 hours, more preferably 8 hours to about 72 hours, depending on the patient, and one or more optional repeat treatments as needed) if the treatment is determined effective in reducing risk of mortality (See Abstract… Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine known to be associated with adverse events in heart failure patients. The use of serelaxin has been shown to affect GDF-15 levels at baseline and decreases in GDF-15 levels over time. Measuring GDF-15 levels allows a healthcare provider to accurately predict pulmonary load in patients with pulmonary congestion, thereby teaching “if the treatment is determined effective in reducing risk of mortality”; Further See Para 0059… Single or multiple administrations of serelaxin formulations may be administered depending on the dosage and frequency as required and tolerated by the patient who suffers from edema and/or NDI. The formulations should provide a sufficient quantity of serelaxin to effectively ameliorate the condition).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gyllensten, Shen and Buendgen to incorporate continuing the therapeutic treatment if the treatment is determined effective in reducing risk of mortality as taught by Prescott, for the benefit of having a serum concentration of serelaxin that provides for the decrease of the GDF-15 levels in blood serum (Prescott , Para 0070-0072, Abstract) wherein changes in GDF-15 mediate the association of serelaxin treatment with decreased 180-day mortality (Prescott , Para 0080), which allows for the disclosure that the use of serelaxin can be used to lower GDF-15 levels in patients with cardiovascular disease, and is particularly useful in lowering GDF-15 levels in patients with acute heart failure. In addition, a method of assessing pulmonary load in a patient with pulmonary congestion was discovered. Lastly, it was discovered that GDF-15 provides a biomarker for assessing pulmonary hemodynamics and informs the diagnosis, prognosis and treatment of heart failure (Prescott, Para 0010).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached on (571) 272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/OYELEYE ALEXANDER ALABI/ Examiner, Art Unit 1797