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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13 and 16-18, drawn to diagnosing systemic inflammation/prognosing risk, in the reply filed on 06/02/2026 is acknowledged. In addition, Applicant has elected the additional biomarker phosphatidylinositol-glycan-specific phospholipase D (PHLD). Claims 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/02/2026.
Claims 1-13 and 16-18 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) 365(c) is acknowledged. Further, receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The priority date of claims 1-13 and 16-18 is 04/13/2021.
Sequence Rules
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). The instant application is not in compliance with the sequence rules, particularly 37 CFR § 1.821(d), which requires that reference be made to a particular sequence identifier (SEQ ID NO: X) in the specification and claims at each disclosure of a sequence encompassed by the definitions set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). Specifically, Table 11 at pages 79-161 contains amino acid sequences without any corresponding sequence identifiers. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 13 recites the limitation “for monitoring the therapeutic success or therapeutic failure” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim since neither claim 12 or claim 1, from which claim 13 ultimately depends, address therapeutic success or failure. Note that this issue could be addressed by amending claim 13 to recite “or further, for monitoring therapy
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 1-13 and 16-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite methods of in vitro diagnosis of systemic inflammation or prognosing a risk of mortality of a subject with a systemic inflammation, wherein the method comprises a) determining the level of soluble V-set and immunoglobulin domain-containing protein 4 (sVSIG4) in a biological sample, and b) drawing a conclusion as to the diagnosis of a systemic inflammation or the prognosis of a risk of mortality of a subject with a systemic inflammation from the presence and/or level of sVSIG4. Since the preamble of claim 1 recites a method of “in vitro diagnosing a systemic inflammation”, the “determining” step is interpreted as performing an assay on a biological sample. The claims are drawn to the statutory category of a process. See Step 1 of the Revised Guidelines.
The first step in determining whether a claim recites patent eligible subject matter is to consider whether the claims recite an abstract idea, law of nature or a natural phenomenon. See Prong One of Step 2A in the Revised Guidelines. Claim 1 recites drawing a conclusion as to the diagnosis or prognosis of a mortality risk, which is a mental step. The dependent claims provide details about whether the inflammation is sepsis resulting from a bacterium, fungus or virus or a sterile infection resulting in a systemic inflammatory reaction syndrome or SIRS, or the sVSIG4 is an extracellular domain (ECD). In addition, claim 9 requires the mental steps determining the level of one or more additional biomarkers and drawing a conclusion as to the diagnosis while claims 10-11 recite many possible additional biomarkers. Note the broadest reasonable interpretation of the “determining” step in claim 9 encompasses reading a result of a chart. Claims 12 and 13 recite monitoring a systemic inflammation comprising performing an in vitro diagnosing according to claim 1 and repeating this step until diagnosing the absence of the systemic inflammation or for monitoring the therapeutic success or failure. Thus claims 9-13 recite additional mental steps of reading results, drawing conclusions about diagnosis and monitoring systemic inflammation and therapeutic success or failure. The mental steps of comparing biomarker levels and drawing conclusions in the instant claims are similar to comparing information regarding a sample or test subject to a control or target data (see Univ. of Utah Research Found, v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014), or diagnosing an abnormal condition by performing clinical tests and thinking about the results (see In re Grams, 12 USPQ2d 1824 (Fed. Cir. 1989). The answer to Prong One Step 2A is yes.
The second step in determining patent-eligibility of claimed subject matter is to consider whether the claims recite additional elements that integrate the judicial exception into a practical application. While the claims are interpreted as requiring performance of an in vitro assay to “determine” sVSIG4 levels, sample collection is merely the necessary data gathering required in order to perform the mental analysis steps of comparison and diagnosis/prognosis. Further, the claims do not recite any particular elements or methods of measuring sVSIG4. The discovery of the relationship between a sVSIG4 and systemic inflammation is not sufficient to integrate the judicial exception into a practical application. See MPEP 2106.04(I), which instructs:
The Supreme Court’s cited rationale for considering even “just discovered” judicial exceptions as exceptions stems from the concern that “without this exception, there would be considerable danger that the grant of patents would ‘tie up’ the use of such tools and thereby ‘inhibit future innovation premised upon them.’” Myriad, 569 U.S. at 589, 106 USPQ2d at 1978-79 (quoting Mayo, 566 U.S. at 86, 101 USPQ2d at 1971). See also Myriad, 569 U.S. at 591, 106 USPQ2d at 1979 (“Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the §101 inquiry.”). The Federal Circuit has also applied this principle, for example, when holding a concept of using advertising as an exchange or currency to be an abstract idea, despite the patentee’s arguments that the concept was “new”. Ultramercial, Inc. v. Hulu, LLC, 772 F.3d 709, 714-15, 112 USPQ2d 1750, 1753-54 (Fed. Cir. 2014). Cf. Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016) (“a new abstract idea is still an abstract idea”) (emphasis in original).
Further, in explaining Prong Two of Step 2A, MPEP 2104.04(II)(A)(2) states patent “eligibility ‘cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself’”. In summary, the judicial exception is not integrated into a practical application because the additional steps constitute mere data gathering. The answer to Prong Two of Step 2A is no.
The final step in determining whether the claims recite patent eligible subject matter is to consider whether the claims recite additional elements that amount to significantly more than the judicial exception. As noted above, the claims do not recite any particular assays or steps. The prior art recognized how to measure soluble VSIG4. For instance, Yuan et al. (British Journal of Haematology, 2020, 189, 72-83) teach soluble VSIG4 is measured using a commercially available enzyme-linked immunosorbent assay (ELISA—see p. 74, left column, under “Soluble VSIG4 measurement by ELISA”). For claims reciting judicial exceptions to be eligible, the additional elements in the claim must “transform the nature of the claim” either at Prong Two or in Step 2B. In the instant case, the additional steps are simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (see MPEP 2106.05(d)).
Thus, the claims are not patent-eligible.
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 1-13 and 16-18 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 the claimed methods in which elevated levels of sVSIG4 indicate the presence of sepsis, or systemic inflammation as indicated in the prior art, does not reasonably provide enablement for the claims as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The claims are broad with respect to how the diagnosis of systemic inflammation or prognosis of a risk of mortality are carried out based on the presence/level of sVSIG4. Specifically, there is no indication in the claims whether sVSIG4 levels are up- or down-regulated. The instant specification teaches soluble VSIG4 is significantly upregulated in patients with sepsis (see p. 59, Table 7; p. 68, Table 8; pages 70-71, Table 9 and Figure 1). In addition, the specification verified sVSIG4 levels and quantitative analysis at pages 75-78:
In summary, the verification experiments by ELISA indicate that by using quantification methods to determine the sVSIG level in patient blood samples (e.g. in plasma) alone, or in combination with other biomarkers, it is possible to diagnostically differentiate patients with severe sepsis or septic shock from patients with SIRS or SIRS+organ dysfunction. Furthermore, high sVSIG4 levels already indicate an increased mortality risk of the patient at an early stage of the disease, so that this patient group can be identified and thus could get an individualized, more intensive monitoring in order to be able to therapeutically intervene at an early stage. sVSIG4 levels are particularly high in plasma in patients with microbiologically positive confirmations of a systemic infection and with high SOFA-score values.
In summary, the specification discloses VSIG4 levels are upregulated in sepsis. Similarly, the prior art of Yuan et al. (cited above) teaches that sVSIG4 levels are elevated in patients with lymphoma-associated hemophagocytic lymphohistiocytosis (L-HLH), a condition characterized by severe inflammation (see abstract; p. 73, left column, 1st paragraph; p. 78, Figure 1B). The evidence in the specification and prior art is not commensurate with the broad scope of the claimed invention. Due to the breadth of the claims which fail to recite limitations on whether sVSIG4 levels are up- or down-regulated, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
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.
Claims 1-5, 9-11 and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yuan et al. (British Journal of Haematology, 01/21/2020, 189, 72-83). Yuan et al. teach that soluble V-set and immunoglobulin domain-containing protein 4 levels (sVSIG4) are elevated in patients with lymphoma-associated hemophagocytic lymphohistiocytosis (L-HLH), a condition characterized by severe inflammation (see abstract; p. 73, left column, 1st paragraph; p. 78, Figure 1B). There are multiple etiologies involved in L-HLH, including “systemic infections, malignancies and autoimmune disorders or immune system iatrogenic treatments” (see p. 73, left column, 1st paragraph). Indeed, Yuan et al. teach that “infection is the leading cause of adult HLH in the US, while malignancy is the leading cause in China” (see p. 73, left column, 1st paragraph). Further, Yuan et al. teach that 4 of the 18 patients with L-HLH tested had bacterial infections (see p. 75, Table I) and that sVSIG4 levels were also higher in patients infected with Epstein Barr Virus (EBV) and L-HLH (see p. 78, left column, top of page). Yuan et al. teach that sVSIG4 may be useful as a biomarker to “refine the prognosis” in patients with L-HLH (see p. 73, right column, 2nd paragraph; p. 78, right column under “Prognostic value of sVSIG4 in patients with lymphoma”). Thus, Yuan et al. meet the limitations of claims 1-5 and 16. Finally, Yuan et al. also teach that at least Macrophage Mannose Receptor 1 (MRC1) was altered in L-HLH (see p. 76, Table II), thereby meeting the limitations of claims 9-11.
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.
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 1-6, 9-13 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al. (cited above) in view of Mostaza-Fernádez et al. (Rev Clin Esp. 2014;214(6):320-327). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Yuan et al. teach that sVSIG4 levels are elevated in patients with lymphoma-associated hemophagocytic lymphohistiocytosis (L-HLH), a condition characterized by severe inflammation (see abstract; p. 73, left column, 1st paragraph; p. 78, Figure 1B). There are multiple etiologies involved in L-HLH, including “systemic infections, malignancies and autoimmune disorders or immune system iatrogenic treatments” (see p. 73, left column, 1st paragraph). Indeed, Yuan et al. teach that “infection is the leading cause of adult HLH in the US, while malignancy is the leading cause in China” (see p. 73, left column, 1st paragraph). Further, Yuan et al. teach that 4 of the 18 patients with L-HLH tested had bacterial infections (see p. 75, Table I) and that sVSIG4 levels were also higher in patients infected with Epstein Barr Virus (EBV) and L-HLH (see p. 78, left column, top of page). Yuan et al. teach that sVSIG4 may be useful as a biomarker to “refine the prognosis” in patients with L-HLH (see p. 73, right column, 2nd paragraph; p. 78, right column under “Prognostic value of sVSIG4 in patients with lymphoma”). Thus, Yuan et al. meet the limitations of claims 1-5 and 16. Finally, Yuan et al. also teach that at least Macrophage Mannose Receptor 1 (MRC1) was altered in L-HLH (see p. 76, Table II), thereby meeting the limitations of claims 9-11.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Yuan et al. do not explicitly teach the systemic inflammation not caused by an infectious agent is systemic inflammatory reaction syndrome (SIRS). In addition, Yuan et al. do not explicitly teach monitoring systemic inflammation or treatment by repeating the diagnosing step of determining soluble VSIG4 levels at least once. These issues will be considered in turn.
(i) Mostaza-Fernádez et al. teach that L-HLH can result from both infectious (viruses, bacteria, fungi) and non-infectious causes (tumors, autoimmune disease) that result in an exaggerated systemic inflammatory reaction or cytokine storm (see p. 323, Figure 2; p. 325, left column, 1st paragraph). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that L-HLH patients could have a systemic inflammation reaction syndrome (SIRS) not caused by an infectious agent because Mostaza-Fernádez et al. teach that this reaction can also occur as a result of non-infectious causes (see p. 323, Figure 2). The person of ordinary skill in the art, upon reading the combined prior art teachings, would understand that SIRS may result from both infectious and non-infectious triggers.
(ii) Regarding repeating the determining soluble VSIG4 levels to diagnose systemic inflammation or monitor treatment, it would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the applied prior teachings by repeating the diagnostic step measuring soluble VSIG4 because it is part of the general motivation in the art to not only diagnose disease, but also monitor its progression and its response to therapy. The person of ordinary skill in the art would have been motivated to use VSIG4 to monitor sepsis progression and treatment because Mostaza-Fernádez et al. that it is important to rule out underlying infections when treating L-HLH (see p. 324, paragraph bridging the left and right columns):
When an infectious disease is suspected, appropriate diagnostic tests should be indicated and appropriate empiric antimicrobial treatment started. If the disease progresses despite these measures, anti-inflammatory and/or immunosuppressive treatment should be established.
The person of ordinary skill in the art would have been motivated to repeat testing sVSIG4 because Mostaza-Fernádez et al. strongly suggest that one repeat testing to rule out infectious as well as non-infectious causes of HLH in order to carry out prognosis and treatment. Finally, the person of ordinary skill in the art could have reasonably expected success because Yuan et al. teach that sVSIG4 has high sensitivity and specificity as a biomarker for diagnosing L-HLH (see p. 78, paragraph bridging left and right columns).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-5, 7-13 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan et al. British Journal of Haematology, 01/21/2020, 189, 72-83) in view of Vogt et al. (J Clin Invest. 2006;116(10):2817-2826) and Gurney (WO2013184912). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Yuan et al. teach that soluble V-set and sVSIG4 are elevated in patients with lymphoma-associated hemophagocytic lymphohistiocytosis (L-HLH), a condition characterized by severe inflammation (see abstract; p. 73, left column, 1st paragraph; p. 78, Figure 1B). There are multiple etiologies involved in L-HLH, including “systemic infections, malignancies and autoimmune disorders or immune system iatrogenic treatments” (see p. 73, left column, 1st paragraph). Indeed, Yuan et al. teach that “infection is the leading cause of adult HLH in the US, while malignancy is the leading cause in China” (see p. 73, left column, 1st paragraph). Further, Yuan et al. teach that 4 of the 18 patients with L-HLH tested had bacterial infections (see p. 75, Table I) and that sVSIG4 levels were also higher in patients infected with Epstein Barr Virus (EBV) and L-HLH (see p. 78, left column, top of page). Yuan et al. teach that sVSIG4 may be useful as a biomarker to “refine the prognosis” in patients with L-HLH (see p. 73, right column, 2nd paragraph; p. 78, right column under “Prognostic value of sVSIG4 in patients with lymphoma”). Thus, Yuan et al. meet the limitations of claims 1-5 and 16. Finally, Yuan et al. also teach that at least Macrophage Mannose Receptor 1 (MRC1) was altered in L-HLH (see p. 76, Table II), thereby meeting the limitations of claims 9-11.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Yuan et al. do not explicitly teach that the soluble VSIG4 comprises the extracellular domain (ECD) or that the ECD comprises SEQ ID NOs: 4, 4-5 or 6. In addition, Yuan et al. do not explicitly teach monitoring systemic inflammation or treatment by repeating the diagnosing step of determining soluble VSIG4 levels at least once. These issues will be considered in turn.
(i) Regarding the sVSIG4 comprising the ECD, Yuan et al. suggest that sVSIG4 sheds in patients with L-HLH (see p. 80, left column, 2nd paragraph). Further, Yuan et al. teach that soluble VSIG4 exists “exclusively on the surface of human and mouse macrophages” (see p. 73, right column, 2nd paragraph). Therefore, Yuan et al. teach that sVSIG4 exists only on the surface of the cells, and that this portion sheds during L-HLH illness, which implies that sVSIG4 circulates in the blood. Vogt et al. teach that cell surface VSIG4 (i.e., soluble portion that is shed) is detected by generating an antibody against the extracellular domain (see p. 2817, right column, 2nd paragraph), thereby providing evidence that Yuan et al. was contacting the ECD to measure sVISG4. Regarding antibodies specific for the VSIG4 ECD, these were known in the art. For example, Gurney suggests antibodies could be generated against SEQ ID NO: 4 (the soluble ECD portion of VSIG4—see paragraphs [008]; [0122]; [0124]-[0125]; claims 1-13). See the alignment between instant SEQ ID NO: 4 and SEQ ID NO: 44 of Gurney:
Query Match 100.0%; Score 602; Length 264;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 PILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQA 61
Qy 61 KYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKIT 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 KYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKIT 112
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the soluble VSIG4 comprises the Ig-like domain I set forth in instant SEQ ID NO: 4 because the applied prior art of Yuan et al. and Vogt et al. strongly suggest that the soluble portion of VSIG4 detected in Yuan and colleagues is the ECD portion of VSIG4. As noted above, Yuan et al. teach measuring sVSIG4, that sVSIG4 exists only on the surface of the cells, and that this portion sheds during L-HLH illness; while Vogt et al. teach that cell surface VSIG4 (i.e., soluble portion that is shed) is detected by generating an antibody against the extracellular domain (see p. 2817, right column, 2nd paragraph). In addition, Gurney discloses antibodies to the same ECD portion as set forth in SEQ ID NO: 4.
The person of ordinary skill in the art would have understood how to determine the level of sVSIG4 by measuring an ECD portion as set forth in instant SEQ ID NO: 4 because the applied prior art strongly suggests these steps. Further, for the record, the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). See also MPEP 2112.
(ii) Regarding repeating the determining soluble VSIG4 levels to diagnose systemic inflammation or monitor treatment, it would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the applied prior teachings by repeating the diagnostic step measuring soluble VSIG4 because it is part of the general motivation in the art to not only diagnose disease, but also monitor its progression and its response to therapy. The person of ordinary skill in the art would have been motivated to use VSIG4 to monitor sepsis progression and treatment because Mostaza-Fernádez et al. that it is important to rule out underlying infections when treating L-HLH (see p. 324, paragraph bridging the left and right columns):
When an infectious disease is suspected, appropriate diagnostic tests should be indicated and appropriate empiric antimicrobial treatment started. If the disease progresses despite these measures, anti-inflammatory and/or immunosuppressive treatment should be established.
The person of ordinary skill in the art would have been motivated to repeat testing sVSIG4 because Mostaza-Fernádez et al. strongly suggest that one repeat testing to rule out infectious as well as non-infectious causes of HLH in order to carry out prognosis and treatment. Finally, the person of ordinary skill in the art could have reasonably expected success because Yuan et al. teach that sVSIG4 has high sensitivity and specificity as a biomarker for diagnosing L-HLH (see p. 78, paragraph bridging left and right columns).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-3, 7-9, 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (KR20180047928—EPO translation provided) in view of Vogt et al. (J Clin Invest. 2006;116(10):2817-2826) and Gurney (WO2013184912). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The translation of Lee teaches diagnosing septicemia comprising measuring the level of VSIG4 (V-set and immunoglobulin-domain containing protein) cell surface antigen expression in a sample isolated from suspected sepsis patients, comparing the level of expression of said VSIG4 cell surface antigen with a sample isolated from normal persons, and diagnosing sepsis when the expression level of the VSIG4 cell surface antigen of the sample suspected of sepsis is higher than that of the normal control sample, wherein the VSIG4 is measured via an antibody through an antigen-antibody reaction carried out by an enzyme immunoassay (ELISA), radioimmunoassay (RIA), a sandwich assay, a western blot, an immunoprecipitation method, among others (see claims). Lee contemplates a patient population in which sepsis occurs as a result of infections (see paragraphs [0002]; [0005] of the Lee translation). Lee also teaches that the expression of other genes increased during sepsis induction, for instance, TIMP1 and CD177 (see paragraph [0064]; Figure 1 of the Lee translation).
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Lee does not explicitly teach that the VSIG4 is a soluble form, although they do teach that the detected VSIG4 is on the cell surface (see claims). In addition, Lee does not explicitly teach monitoring systemic inflammation or treatment by repeating the diagnosing step of determining soluble VSIG4 levels at least once. These issues will be considered in turn.
(i) Regarding measuring the soluble form of VSIG4, Lee teaches measuring cell surface sVSIG4 (see claims) and Vogt et al. teach that cell surface VSIG4 is detected by generating an antibody against the extracellular domain (see p. 2817, right column, 2nd paragraph), thereby providing evidence that Lee was contacting the extracellular domain to measure sVSIG4. Regarding antibodies specific for the VSIG4 ECD, these were known in the art. For example, Gurney suggests antibodies could be generated against SEQ ID NO: 4 (the soluble ECD portion of VSIG4—see paragraphs [008]; [0122]; [0124]-[0125]; claims 1-13). See the alignment between instant SEQ ID NO: 4 and SEQ ID NO: 44 of Gurney:
Query Match 100.0%; Score 602; Length 264;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 PILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQA 61
Qy 61 KYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKIT 111
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Db 62 KYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKIT 112
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the soluble VSIG4 comprises the Ig-like domain I set forth in instant SEQ ID NO: 4 because the applied prior art of Lee and Vogt et al. strongly suggest that the soluble portion of VSIG4 detected in Lee is the ECD portion of VSIG4. As noted above, Lee teaches VSIG4 detected is on the cell surface, while Vogt et al. teach that cell surface VSIG4 is detected by generating an antibody against the extracellular domain (see p. 2817, right column, 2nd paragraph). In addition, Gurney discloses antibodies to the same ECD portion as set forth in SEQ ID NO: 4. The person of ordinary skill in the art would have understood how to determine the level of sVSIG4 by measuring an ECD portion as set forth in instant SEQ ID NO: 4 because the applied prior art strongly suggests these steps. Further, for the record, the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). See also MPEP 2112.
(ii) Regarding repeating the determining soluble VSIG4 levels to diagnose systemic inflammation or monitor treatment, it would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the applied prior teachings by repeating the diagnostic step measuring soluble VSIG4 because it is part of the general motivation in the art to not only diagnose disease, but also monitor its progression and its response to therapy. The person of ordinary skill in the art would have been motivated to use VSIG4 to monitor sepsis progression and treatment because Lee suggests a screening method for testing sepsis treatments and selecting substances in which the degree of VSIG4 expression is reduced (see claim 10 and paragraphs [0011], [0016], [0053] of the translation). Such a screening method mirrors the steps of monitoring therapeutic success as recited in claim 12. Finally, the person of ordinary skill in the art could have reasonably expected success because Lee teaches that sVSIG4 was effective as a biomarker for diagnosing sepsis in a mouse model (see paragraphs [0032]; [0071]-[0072]; [0076]; [0088]).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 4-6 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lee, Vogt et al. and Gurney as applied to claims 1-3, 7-9, 11-13 above, and further in view of Vincent et al. (Lancet 2013; 381: 774-75), Yuan et al. (cited above) and Mostaza-Fernádez et al. (cited above). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Lee, Vogt et al. and Gurney and how they meet the limitations of claims 1-3, 7-9, 11-13 are outlined above in the preceding rejection and are hereby incorporated.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Lee, Vogt et al. and Gurney do not address specific infectious and non-infectious triggers of systemic inflammation. Vincent et al. teach sepsis may be caused by bacterial, viral or fungal infections (see p. 775, right column). Nevertheless, a common reaction to sepsis, systemic inflammatory response syndrome or SIRS, may also have non-infectious causes (see p. 774, left column, 2nd – 3rd paragraphs of Vincent and colleagues). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that both infectious and sterile products can result in SIRS because Vincent et al. teach “[i]nfectious and non-infectious stimuli that activate innate immunity and cytokine release and can cause sepsis” (see Figure at p. 774). The person of ordinary skill in the art would have recognized the overlap in causative agents that can lead to sepsis because Vincent et al. teach (p. 774, right column, 3rd paragraph):
Whether this syndrome is mediated by endogenous endotoxin or by non-infectious stimuli can be very difficult to define. However, we know that sepsis arises through activation of an innate immune response to a stimulus that represents a danger to the host. From a molecular perspective, the initial host response to infection does not differ appreciably from the host response to sterile inflammation from severe trauma, burns, ischaemic reperfusion injury, or other forms of tissue injury that are accompanied by cell necrosis. (Citations omitted by examiner).
The person having ordinary skill in the art could have reasonably expected success because the prior art teachings of Yuan et al. and Mostaza-Fernádez et al. suggest that soluble VSIG4 is an appropriate biomarker for both infectious and sterile causes of L-HLH (see abstract; p. 73, left column, 1st paragraph; p. 78, Figure 1B of Yuan and colleagues and p. 323, Figure 2; p. 325, left column, 1st paragraph of Mostaza-Fernádez and colleagues). In summary, the sequalae of sepsis and SIRS (an exaggerated systemic inflammatory reaction or cytokine storm) overlap significantly regardless of whether the inducing agent is infectious or sterile, and the combined prior art teachings also suggest soluble VSIG4 is an effective biomarker in both infectious (Lee) and non-infectious (Yuan et al. and Mostaza-Fernádez et al.) systemic inflammation.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Lee, Vogt et al. and Gurney as applied to claims 1-3, 7-9, 11-13 above, and further in view of Lin et al. (PLoS ONE 12 (5): e0178387. https://doi.org/10.1371/journal. pone.0178387). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Lee, Vogt et al. and Gurney and how they meet the limitations of claims 1-3, 7-9, 11-13 are outlined above in a preceding rejection and are hereby incorporated.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Lee, Vogt et al. and Gurney do not teach the additional biomarker is kallistatin et al., for example. Lin et al. teach plasma kallistatin may be measured in patients to diagnose septic shock severity (see abstract; p. 9, Figure 2). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the combined teachings of Lee, Vogt et al. and Gurney by adding kallistatin as a biomarker because it can act as a prognostic biomarker, namely, elucidating severity of disease, since higher levels are associated with good outcome and lower levels are associated with poor outcome (see p. 11, last paragraph). The person of ordinary skill in the art would have been motivated to use kallistatin as an additional biomarker because it can “refine risk stratification” (see p. 11, last paragraph). Furthermore, the person of ordinary skill in the art could have reasonably expected success for this reason as well.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
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