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 .
Priority
Independent claims 1, 13, and 16 all recite cytokines which include TNF-α, IL-10, IL-4, IL-8, and IL-2. Measuring these cytokines is not disclosed until U.S. Provisional Application 63/334,218 filed April 25, 2022.
Thus, all claims are examined with the effective filing date of April 25, 2022.
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 1-3, 7-12, 16, and 18-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more.
Claims 1-3 and 7-12 recite a method of assessing and treating traumatic brain injury comprising obtaining a biological sample, determining the amount of inflammatory cytokine in the sample, determining whether that amount falls beyond a cut-off value and administering a composition which inactivates or neutralizes the amount of inflammatory cytokine such that the amount is increased or decreased. Claims 1-12 recite a natural phenomenon in which inflammatory cytokines increase following traumatic head injury. This judicial exception is not integrated into a practical application because the administration of the composition is only administered “when” the inflammatory cytokine or inflammasome protein is determined to be outside the cut-off value. In other words, the judicial exception may be applied to a given patient in the steps of obtaining and determining, but the administering step is not completed “when” the patient’s inflammatory cytokine or inflammasome protein is determined to be inside the cut-off value. Moreover, the compositions recited in claim 1 is not a particular treatment “i.e., specifically identified so that it does not encompass all applications of the judicial exception(s)”; see MPEP 2106.04(d)(2)(a). The compositions of claims 8-10, excluding the sequences of claims 9 and 10 which are identified as not enabled, are particular treatments. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because obtaining and determining the amount of an inflammatory cytokine in a sample are extra-solution data gathering activities and comparing a level to a reference range or cut-off value is routine and conventional; see Di Iorio et al. (Cytokine. 22: 198-205; Published: June 21, 2003), Zhu et al. (Journal of the American Geriatrics Society. 57(9): 1672-1677; Published: September 2009), and Dunlay et al. (Circulation. 118(6): 625-631; Published: July 21, 2008).
Claims 16 and 18-22 recite determining the prognosis for a patient with traumatic brain injury comprising obtaining a biological sample and measuring the level of at least one inflammasome protein in the biological sample. Similar to claims 1-12, claims 16-19 recite a natural phenomenon in which inflammasome proteins increase following traumatic head injury. This judicial exception is not integrated into a practical application because, similar to claims 1-12, the patient is only administered a composition when outside a clinically established cut-off value. Moreover, the compositions recited in claim 16 is not a particular treatment “i.e., specifically identified so that it does not encompass all applications of the judicial exception(s)”; see MPEP 2106.04(d)(2)(a). The compositions of claims 20 and 22, excluding the sequences of claims 9 and 10 which are identified as not enabled, are particular treatments The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the method requires only two steps: obtaining the sample and measuring the level of inflammasome protein. The step of obtaining the sample is merely an extra-solution activity.
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.
Claims 1-3, 7-13, 16, and 18-22 are 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 1 recites determining whether an inflammatory cytokine of inflammasome protein is “above a maximum or below a minimum” predetermined cut-off value and includes a table. It is unclear how to apply the table and the limitation “above a maximum or below a minimum” predetermined cut-off value. The table includes a value for each cytokine or protein, but this is actually a threshold. For example, the table says for capase-1 >0.8150 pg/ml, which is interpreted as infinity to 0.8150 pg/ml. In this instance, 0.8150 pg/ml is the minimum value of the threshold. But the limitation says “below a minimum”, so is one determining the inverse of what is in the table? The claim later says administering when the cytokine or protein is “outside the cut-off value”. It is unclear what is outside. In the case of caspase-1, does outside mean above 0.8150 pg/ml (i.e. within the range) or below 0.8150 pg/ml? For the purpose of compact prosecution, claim 1 is interpreted as determining if a value is within the thresholds in the table, and administering a composition if it is outside of the corresponding threshold in the table. If this interpretation is correct, then in place of “above a maximum or below a minimum pre-determined cut-off-value” it may be more clear to say within a pre-determined threshold.
Additionally, claim 10 recites “one or more small molecule[s] selected from the group consisting of […] resveratrol, and other glutamate receptor antagonists and an antioxidant and one or more antibody or antibody fragments […]”. It is unclear whether the claim requires three things: 1. One or more small molecules, 2. An antioxidant, and 3. An antibody or antibody fragment; or if the claim requires only two things 1. One or more small molecules, 2. An antibody or antibody fragment and “an antioxidant” is included in the group of small molecules. For the purpose of compact prosecution, the antioxidant is interpreted as being part of the group of small molecules.
Claim 13 is amended to recite “a labeled-binding partner that specifically binds to each of said inflammatory cytokines or inflammasome proteins”, but then recites “selected from the group” and “combinations thereof”. The two latter limitations and the use of “or” between inflammatory cytokines and inflammasome proteins, contradict the “each of” recited earlier in the claim. For the purpose of compact prosecution, the claim is interpreted as requiring a binding partner for each of the recited cytokines (i.e. the interleukins and TNF-alpha) or inflammasome proteins (i.e. caspase-1 and ASC).
Claim 16 recites a composition which “inactivates or neutralizes the amount of inflammatory cytokine such that the amount of inflammatory cytokine is increased or decreased”. Inactivate or neutralize convey a physical antagonistic inhibition of the activity of an inflammatory cytokine. One may reason that an antagonistic antibody comprising an Fc region and targeting a cytokine would both inactivate or neutralize the activity and decrease the amount as bound cytokine is targeted for phagocytosis and degradation. However, it is unclear how a composition may inactivate or neutralize an amount. For the purpose of compact prosecution, the composition of claim 16 is interpreted as decreasing or increasing the amount of inflammatory cytokine or inflammasome protein.
Claim 16 recites “selecting a treatment regimen based upon the determined prognosis of the patient”. It is unclear if “a treatment regimen” in the selecting step is the same as “a composition selected to inactivate or neutralize” in the administering step. For the purpose of compact prosecution, “a treatment regimen” is interpreted to include “a composition selected to inactivate or neutralize”, but is not limited to only “a composition selected to inactivate or neutralize”.
Claims 2, 3, and 7-12 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claims 18-22 are rejected for depending from claim 16 and failing to remedy the indefiniteness.
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 9, 10, 21, and 22 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:
treating traumatic brain injury comprising administering a composition which decreases the synthesis of an inflammatory cytokine, wherein said composition comprises an antibody or fragment thereof which comprises either: 1. SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or 2. One of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31,
does not reasonably provide enablement for:
treating traumatic brain injury comprising administering a composition which inactivates or neutralizes the amount of inflammatory cytokine, wherein said composition comprises an antibody or fragment thereof which comprises any one of SEQ ID NOs: 6, 7, 8, 12, 13, 14, 18, 19, 20, 21, 22, 28, 29, 30, or 31.
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.
The composition which inactivates or neutralizes the amount of inflammatory cytokine is indefinite. The claim is interpreted as reciting the composition that increases or decreases the amount of an inflammatory cytokine. This is a broad genus of compositions which encompass small molecule inhibitors of cytokines or aptamers or antagonist antibodies of fragments thereof which bind cytokines. In particular, this rejection focuses on the antibody or fragments thereof comprising one or more of the SEQ ID NOs recited in claims 9 and 10.
The nature of the invention is that inflammatory cytokines or inflammasome proteins become elevated following traumatic brain injury and these elevated inflammatory cytokines or inflammasome proteins are associated with poor prognosis. The invention aims to treat patients having traumatic head injury with a composition which reduces the amount of inflammatory cytokine or neutralizes the activity of an inflammatory cytokine. Regarding the sequences of claims 9, 10, 21, and 22, no sequence recited is associated with an antibody capable of directly binding an inflammatory cytokine. Further, only SEQ ID NOs: 6-8, 12-14, 18-22, and 28-31 are sequences which comprise an antibody. SEQ ID NO: 18-22 are anti-ASC antibody VH sequences. SEQ ID NOs: 28-31 are anti-ASC antibody VL sequences. SEQ ID NOs: 6-8 and 12-14 are CDRs of an anti-ASC antibody.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (PNAS. 79: 1979-1983; Published: March 15, 1982). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
MacCallum et al. (Journal of Molecular Biology. 262(5): 732-745; Published: October 11, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations; see page 733 right column and page 735 left column.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307(1): 198-205; Published: July 18, 2003), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs. Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3; see page 199 left column and page 202 left column.
Padlan et al. (PNAS. 86: 5938-5942; Published: August 1, 1989) describes the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen.
Lastly, Lamminmaki et al. (Journal of Biological Chemistry. 276(39): 36687-36694; Published: September 28, 2001) describes the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen - even CDR2 of VL, which is rarely directly involved in hapten binding.
The disclosure of U.S. Application 17/921,600 teaches anti-ASC antibodies comprising the six CDRs of SEQ ID NOs: 6-8 and 12-14 or the VH and VL pairs of SEQ ID NOs: 18-22 and 28-31. The disclosure does not teach that a protein comprising a single CDR nor a single VH or VL is capable of binding ASC – an action necessary to reduce the amount of an inflammatory cytokine. No further guidance regarding antibody sequences is provided in the instant disclosure.
While the level of skill in the art is high, the unpredictability in the art is also high as demonstrated by Rudikoff et al., MacCallum et al., Casset et al., Padlan et al., and Lamminmaki et al. The remaining structure of an antibody which increases or decreases the amount of inflammatory cytokine and comprises only one of the CDRs of SEQ ID NOs: 6-8 and 12-14 or the VH and VL pairs of SEQ ID NOs: 18-22 and 28-31 is unpredictable.
The amount of experimentation necessary to practice the claimed method in accordance with its scope of an antibody comprising a single SEQ ID NO recited would be enormous. One would have to identify sequences for the remaining 5 CDRs or sequences for the VH or VL pair which yields an antibody then assay whether that antibody is capable of increasing or decreasing the amount of inflammatory cytokine.
Given the high level of unpredictability, the limited guidance in the Specification, and the disclosure of only a single antibody, it would more than reasonable experimentation to make or use the invention commensurate in scope with the claims.
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.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol (EMD Millipore Corporation; Published: May 24, 2017) in view of Dai et al. (Journal of Allergy and Clinical Immunology. 127(3): 806-814; Published: January 26, 2011).
Claim 13 recites a kit comprising a labeled binding partner which binds to one or more of caspase-1, ASC, IL-18, TNF-α, IL-6, IL-4, IL-10, IL-8, IL-2, or IL-1β. Note the “for preparing an inflammatory cytokine profile associated with TBI” is intended use.
Regarding claim 13, the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol teaches that the kit can be used for the simultaneous quantification of the following 41 human cytokines and chemokines in human tissue/cell lysate and culture supernatant samples and serum or plasma samples: EGF, Eotaxin, G-CSF, GM-CSF, IFNα2, IFNγ, IL-10, IL-12P40, IL-12P70, IL-13, IL-15, IL-17A, IL-1RA, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, TNFα, TNFβ, VEGF,FGF-2, TGF-α, FIT-3L, Fractalkine, GRO, MCP-3, MDC, PDGF-AA, PDGF-AB/BB, sCD40L, and IL-9; see top of page 3 using footer numbers.
Regarding claim 13, the protocol further teaches that the kit “uses proprietary techniques to internally color-code microspheres with two fluorescent dyes. Through precise concentrations of these dyes, distinctly colored bead sets of 500 5.6 μm polystyrene microspheres or 80 6.45 μm magnetic microspheres can be created, each of which is coated with a specific capture antibody.”
The Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol does not teach a binding partner for IL-18, caspase-1, nor ASC.
Dai et al. teaches that inflammasome activation in keratinocytes mediates mite allergen response. Dai et al. uses antibodies against caspase-1, IL-1β, IL-18, ASC, and IL-8 to assess inflammasome activation; see ‘ELISA’ and ‘Protein isolation and Western blotting’ sections.
Because the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol teaches that it can be used with cell lysates and supernatants and because Dai et al. in studying inflammasome activation used antibody-based protein quantification techniques for assessing expression of caspase-1, IL-1β, IL-18, ASC, and IL-8, it would have been obvious to one of ordinary skill in the art to modify the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol to include caspase-1, IL-18, and ASC. The inflammasome is associated with autoinflammatory skin rashes, contact hypersensitivity, allergic diseases, and bacterial infections. One would be motivated to modify to the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol to include caspase-1, IL-18, and ASC in order to more easily study inflammasome activation and inflammation in inflammasome implicated diseases.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1, 7, 11, 12, 16, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) and Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004).
Regarding claim 1, Wang et al. teaches a similar method comprising measuring the level of biomarker in a biological sample and diagnosing a neurological condition, including brain injury, based on the ratio of the biomarker; see claims 1, 5 and 6. In paragraph 0006, Wang et al. teaches that this method can be used to determine severity, predict outcomes, and guide therapy. Wang et al. teaches that severe brain injury is distinguishable by a ratio of 2 comparing the measured level to a relative baseline level; see paragraphs 0012-0014. And the baseline level is the level of the biomarkers in the absence of the neurological condition or a normal reference range; see paragraphs 0061 and 0063. Similarly, the method of claims 16, 18, and 19 comprises two steps: obtaining a biological sample and measuring the level of at least one biomarker (i.e. an inflammasome protein) in the sample, wherein a level outside of the cut-off value is indicative of the prognosis.
Regarding claim 11, Wang et al. teaches that biological samples include CSF, blood, plasma, serum, saliva and urine. While tissue samples may be used, Wang et al. discourages tissues samples as they are “invasive and traumatizing”; see paragraphs 0054-0056.
Regarding claim 12, Wang et al. teaches that the method of measuring biomarkers to diagnose TBI severity or predict a patients prognosis can also be measured to “guide therapy of the condition, as well as monitor subject responsiveness and recovery” and serve as a “surrogate marker of therapeutic interventions”; see paragraphs 0006-0007.
Wang et al. does not teach using inflammatory cytokines as biomarkers for diagnosing neurological conditions.
Regarding claims 16 and 18, Chiaretti et al. teaches that elevated IL-1β and IL-6 plasma and CSF levels were associated with more severe head injury and poor outcome; see page 188 right column. Regarding “within a week” in claim 16, Chiaretti et al. collected plasma and CSF samples and measured the level of IL-1β and IL-6 at 2 hours and 24 hours post-TBI; see ‘Cytokine determination’ section. Regarding claim 19, the patients assessed were aged 3 months to 16 years; see ‘Study population […]’ section. Regarding the cut-off level of claim 16, Chiaretti et al. provides the IL-1β and IL-6 levels stratified by GCS>3 and GCS≤3 (poor outcome) at the 2-hour and 24-hour post-TBI collection; see Figure 5.
Regarding claims 1, 7, and 11, given that Wang et al. teaches a method of measuring a biomarker, comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury, and administering a therapeutic to alter the ratio of biomarker and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and suggests that measuring plasma and CSF interleukin amounts could identify the subset of patients having more pronounced neuroinflammation and who would benefit from glucocorticoids or other anti-inflammatory therapies (see page 191), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample, determine that the amount of IL-1β or IL-6 exceeds the cut-off value, and administer an agent which alters (i.e. increases or decreases) the amount of IL-1β or IL-6.
Further, regarding the cut-off values recited in claim 7, Chiaretti et al. demonstrates that inflammatory cytokine levels are dynamic (i.e. changing over time post-injury) and differ depending on the biological sample. It would have been obvious to one of ordinary skill in the art to determine the cut-off value for IL-1β and IL-6 in pediatric patients with TBI for a given biological sample at a particular time post-injury. Indeed, Wang et al. provides guidance for determining the cut-off value correlated to severity of TBI; see paragraphs 0060-0062. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Moreover, regarding claim 12, given that Wang et al. teaches that the method of measuring the biomarker can be used to monitor treatment response and administering a therapeutic which alters the biomarker ratio and Chiaretti et al. teaches treating the subset of patients with pronounced neuroinflammation with glucocorticoids or other anti-inflammatory therapies (which reduce the amount of inflammatory cytokines), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample following treatment for TBI, wherein a reduction in the amount of IL-1β or IL-6 is indicative of a positive treatment response.
Regarding claims 16, 18, and 19, given that Wang et al. teaches a method of measuring a biomarker and comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and poor outcomes, it would have been obvious and one would have had a reasonable expectation of success to use the interleukin levels from the data provided in Figure 5 to create a cut-off value using the upper threshold of patients having GOS>3 outcomes to compare to plasma and CSF levels in other TBI patients, wherein a level less than the upper threshold or cut-off value is predictive of favorable outcome.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) as applied to claim(s) 1, 7, 11, 12, 16, 18, and 19 above, and further in view of Dickinson et al. (U.S. 7,714,120 B2; Published: May 11, 2010).
The teachings of Wang et al. and Chiaretti et al. as related to claim(s) 1, 7, 11, 12, 16, 18, and 19, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Wang et al. nor Chiaretti et al. teach administering a small molecule or antibody which neutralizes or inactivates an inflammatory cytokine and reduces or increases the amount of an inflammatory cytokine.
Dickinson et al. teaches a neutralizing anti-IL-1β antibody which inhibits the activity of IL-1β; see column 2 lines 52-67. Further, Dickinson et al. teaches that the anti-IL-1β antibodies can be used to treat neuroinflammation associated with stroke and ischemic, excitotoxic, and traumatic head injury; see column 33 lines 24-30. Regarding the ability of anti-IL-1β to increase or decrease the amount of inflammatory cytokine, Table 5 demonstrates that the amount of IL-6 decreased with increasing doses of anti-IL-1β antibody.
Given that Dickinson et al. teaches treating TBI with the anti-IL1β antibody and that the anti-IL-1β antibody decreases the amount of IL-6, an inflammatory cytokine, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer the anti-IL-1β antibody to a patient with TBI and an elevated level of IL-1β and IL-6 as taught by Wang et al. and Chiaretti et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) as applied to claim(s) 1, 7, 11, 12, 16, 18, and 19 above, and further in view of Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004).
The teachings of Wang et al. and Chiaretti et al. as related to claim(s) 1, 7, 11, 12, 16, 18, and 19, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Wang et al. nor Chiaretti et al. teach that inflammatory cytokines are elevated in TBI in adult patients.
Similar to Chiaretti et al., Hayakata et al. teaches that in adults with TBI, the level of inflammatory cytokine changes over time post-injury and differs depending on the biological sample assayed: see Figure 2. Additionally, Hayakata et al. teaches that the peak level of inflammatory cytokines can be associated with severe TBI and outcome; see Table 3.
It would have been obvious to one of ordinary skill in the art and one would have a reasonable expectation of success to apply the method taught by Wang et al. and Chiaretti et al. to adult patients with TBI because Hayakata et al. demonstrates that trends in inflammatory cytokine levels seen in pediatric patients with TBI are similarly seen in adult patients with TBI.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 8 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) as applied to claim(s) 1, 7, 11, 12, 16, 18, and 19 above, and further in view of Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995) and Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011).
The teachings of Wang et al. and Chiaretti et al. as related to claim(s) 1, 7, 11, 12, 16, 18, and 19, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Wang et al. nor Chiaretti et al. teach administering one of the small molecules recited in claims 8 or 20.
Fang et al. teaches that propofol is the most common sedative agent used for patients with TBI; see page 5 left column.
As evidenced by Orser et al. propofol functions as a glutamate receptor antagonist or NMDA receptor antagonist; see Abstract. Additionally, as evidenced by Tang et al., propofol suppresses the secretion of IL-1β, IL-6, and TNF-α; see Abstract.
Given that propofol is the most common sedative administered to TBI patients, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer propofol to a patient with TBI. As evidenced by Orser et al. and Tang et al., propofol is a composition which decreases the amount of inflammatory cytokine and functions as a glutamate or NMDA receptor antagonist.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 9 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) as applied to claim(s) 1, 7, 11, 12, 16, 18, and 19 above, and further in view of Keane et al. (WO 2020/010273 A1; Published: January 09, 2020).
The teachings of Wang et al. and Chiaretti et al. as related to claim(s) 1, 7, 11, 12, 16, 18, and 19, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Wang et al. nor Chiaretti et al. teach administering an anti-ASC antibody comprising one or more of the SEQ ID NOs recited in claims 9 or 21.
Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31; see Table 2 and claims 2-27. Further, Keane et al. teaches that the anti-ASC antibodies are used in methods of treating TBI and reduce the level of inflammatory cytokine; see claims 37-41 and Figure 8.
Given that Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31 and that these antibodies can be administered to teach TBI, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer the anti-ASC antibody to treat TBI.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 10 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2011/0082203 A1; Published: April 7, 2011) and Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) as applied to claim(s) 1, 7, 11, 12, 16, 18, and 19 above, and further in view of Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995) and Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011) and Keane et al. (WO 2020/010273 A1; Published: January 09, 2020).
The teachings of Wang et al. and Chiaretti et al. as related to claim(s) 1, 7, 11, 12, 16, 18, and 19, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Wang et al. nor Chiaretti et al. teach administering one of the small molecules recited in claims 10 or 22 in combination with an anti-ASC antibody comprising one or more of the SEQ ID NOs recited in claims 10 or 22.
Fang et al. teaches that propofol is the most common sedative agent used for patients with TBI; see page 5 left column. As evidenced by Orser et al. propofol functions as a glutamate receptor antagonist or NMDA receptor antagonist; see Abstract. Additionally, as evidenced by Tang et al., propofol suppresses the secretion of IL-1β, IL-6, and TNF-α; see Abstract.
Fang et al., Orser et al., nor Tang et al. teach administering an anti-ASC antibody comprising one or more of the SEQ ID NOs recited in claims 10 or 22.
Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31; see Table 2 and claims 2-27. Further, Keane et al. teaches that the anti-ASC antibodies are used in methods of treating TBI and reduce the level of inflammatory cytokine; see claims 37-41 and Figure 8.
Because both propofol and the anti-ASC antibodies taught by Keane et al. are taught to be used in the treatment of TBI and the reduction of inflammatory cytokine naturally flows from the administration of each, it would have been obvious to one of ordinary skill in the art to administer both propofol and the anti-ASC antibody taught by Keane et al. for the treatment of TBI. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13, 16, 18, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-25, 27, 29, and 32 of copending Application No. 18/347,108 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 13, copending claims 20-23 teach a kit comprising labeled binding partners or antibodies which bind to caspase-1 and ASC.
Regarding instant claims 16 and 18, copending claims 24, 25, 27, and 29 teach a method of determining the prognosis of a patient with TBI by measuring the level of NLRP1, ASC, or caspase-1 in a CSF sample and comparing that level with a pre-determined reference range wherein an elevated level of one inflammasome protein is indicative of poor prognosis. Regarding instant claim 19, copending claim 32 teaches the patient is a pediatric patient.
Thus, copending claim 20-25, 27, and 29 read on instant claims 13, 16, 18, and 19 in an anticipatory manner.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 7, 8, 11, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 15, 18, and 19 of copending Application No. 18/347,108 in view of Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) and Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004).
Regarding instant claim 1, copending claims 1, 6, and 7 teach a method of evaluating and treating TBI comprising obtaining a biological sample, measuring the level of NLRP1, ASC, or caspase-1, determining whether the level is elevated compared to a pre-determined value, and administering a neuroprotective treatment. Regarding instant claim 8, copending claim 18 teaches administering methylprednisolone, for example. Copending claim 15 teaches using the method to treat pediatric patients. Regarding instant claim 11, copending claim 1 recites that the biological sample is CSF. Additionally, regarding instant claim 12, copending claim 19 teaches measuring the level of following treatment wherein a decrease in inflammasome protein following treatment indicates a positive response.
While the copending claims teach measuring the inflammasome proteins NLRP1, ASC, or caspase-1, the copending claims do not teach measuring inflammatory cytokines as indefinite instant claim 1 is interpreted to recite.
Chiaretti et al. teaches that elevated IL-1β and IL-6 plasma and CSF levels were associated with more severe head injury and poor outcome; see page 188 right column. Chiaretti et al. collected plasma and CSF samples and measured the level of IL-1β and IL-6 at 2 hours and 24 hours post-TBI; see ‘Cytokine determination’ section. The patients assessed were aged 3 months to 16 years; see ‘Study population […]’ section.
Neither the copending claims nor Chiaretti et al. teach that the method can be used on an adult patient.
Regarding instant claim 3, similar to Chiaretti et al., Hayakata et al. teaches that in adults with TBI, the level of inflammatory cytokine changes over time post-injury and differs depending on the biological sample assayed: see Figure 2. Additionally, Hayakata et al. teaches that the peak level of inflammatory cytokines can be associated with severe TBI and outcome; see Table 3.
Because the inflammasome, specifically active caspase-1, cleaves IL-1β and because Chiaretti et al. and Hayakata et al. teach that IL-1β and IL-6 are elevated following TBI and the magnitude of elevation is correlated with TBI severity and poor prognosis, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method taught by the copending claims to measure inflammatory cytokine, including IL-1β and IL-6. Further, because both Chiaretti et al. and Hayakata et al. teach similar inflammatory cytokine trends in adult and pediatric patients with TBI, it would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to use the modified method taught by the copending claims in view of Chiaretti et al. and Hayakata et al. to assess and treat both adult and pediatric patients.
Further, regarding the cut-off values recited in claim 7, Chiaretti et al. and Hayakata et al. each demonstrate that inflammatory cytokine levels are dynamic (i.e. changing over time post-injury) and differ depending on the biological sample. It would have been obvious to one of ordinary skill in the art to determine the cut-off value for IL-1β and IL-6 in adult and pediatric patients with TBI for a given biological sample at a particular time post-injury. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
This is a provisional nonstatutory double patenting rejection.
Claim 2 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 15, 18, and 19 of copending Application No. 18/347,108 in view of Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) and Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004) as applied to claim(s) 1, 3, 7, 8, 11, and 12 above, and further in view of Dickinson et al. (U.S. 7,714,120 B2; Published: May 11, 2010).
The teachings of Application No. 18/347,108 in view of Chiaretti et al. and Hayakata et al. as related to claim(s) 1, 3, 7, 8, 11, and 12 from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither the claims of Application No. 18/347,108 nor Chiaretti et al. or Hayakata et al. teach administering an agent which binds and neutralizes or inactivates an inflammatory cytokine.
Dickinson et al. teaches a neutralizing anti-IL-1β antibody which inhibits the activity of IL-1β; see column 2 lines 52-67. Further, Dickinson et al. teaches that the anti-IL-1β antibodies can be used to treat neuroinflammation associated with stroke and ischemic, excitotoxic, and traumatic head injury; see column 33 lines 24-30. Regarding the ability of anti-IL-1β to increase or decrease the amount of inflammatory cytokine, Table 5 demonstrates that the amount of IL-6 decreased with increasing doses of anti-IL-1β antibody.
Given that Dickinson et al. teaches treating TBI with the anti-IL1β antibody and that the anti-IL-1β antibody decreases the amount of IL-6, an inflammatory cytokine, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer the anti-IL-1β antibody to a patient with TBI and an elevated level of IL-1β and IL-6 as taught by copending claims, Chiaretti et al., and Hayakata et al.
Claims 9 and 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 15, 18, and 19 of copending Application No. 18/347,108 in view of Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004) and Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004) as applied to claim(s) 1, 3, 7, 8, 11, and 12 above, and further in view of Keane et al. (WO 2020/010273 A1; Published: January 09, 2020).
The teachings of Application No. 18/347,108 in view of Chiaretti et al. and Hayakata et al. as related to claim(s) 1, 3, 7, 8, 11, and 12, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither the claims of Application No. 18/347,108 nor Chiaretti et al. or Hayakata et al. teach administering an anti-ASC antibody comprising one or more of the SEQ ID NOs recited in claim 9.
Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31; see Table 2 and claims 2-27. Further, Keane et al. teaches that the anti-ASC antibodies are used in methods of treating TBI and reduce the level of inflammatory cytokine; see claims 37-41 and Figure 8.
Given that Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31 and that these antibodies can be administered to teach TBI, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer the anti-ASC antibody to treat TBI.
Because both copending claims 1 and 18 teach administering the agents in copending claim 18 for TBI and the anti-ASC antibodies taught by Keane et al. are taught to be used in the treatment of TBI and the reduction of inflammatory cytokine naturally flows from the administration of each, it would have been obvious to one of ordinary skill in the art to administer both propofol and the anti-ASC antibody taught by Keane et al. for the treatment of TBI. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claim 13 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-25, 27, 29, and 32 of copending Application No. 18/347,108 in view of the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol (EMD Millipore Corporation; Published: May 24, 2017) and Dai et al. (Journal of Allergy and Clinical Immunology. 127(3): 806-814; Published: January 26, 2011).
The copending claims do not teach a kit comprising labeled binding partners for IL-18, IL-1β, TNF-α, IL-6, IL-4, IL-10, IL-8, or IL-2.
The Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol teaches that the kit can be used for the simultaneous quantification of the following 41 human cytokines and chemokines in human tissue/cell lysate and culture supernatant samples and serum or plasma samples: EGF, Eotaxin, G-CSF, GM-CSF, IFNα2, IFNγ, IL-10, IL-12P40, IL-12P70, IL-13, IL-15, IL-17A, IL-1RA, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, TNFα, TNFβ, VEGF,FGF-2, TGF-α, FIT-3L, Fractalkine, GRO, MCP-3, MDC, PDGF-AA, PDGF-AB/BB, sCD40L, and IL-9; see top of page 3 using footer numbers.
Neither the copending claims nor the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol does not teach a binding partner for IL-18.
Dai et al. teaches that inflammasome activation in keratinocytes mediates mite allergen response. Dai et al. uses antibodies against caspase-1, IL-1β, IL-18, ASC, and IL-8 to access inflammasome activation; see ‘ELISA’ and ‘Protein isolation and Western blotting’ sections.
Because the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol teaches that it can be used with cell lysates and supernatants and because Dai et al. in studying inflammasome activation used antibody-based protein quantification techniques for assessing expression of caspase-1, IL-1β, IL-18, ASC, and IL-8, it would have been obvious to one of ordinary skill in the art to modify the kit of the copending claims to include IL-18, IL-1β, TNF-α, IL-6, IL-4, IL-10, IL-8, or IL-2. The inflammasome is associated with autoinflammatory skin rashes, contact hypersensitivity, allergic diseases, and bacterial infections. One would be motivated to modify to the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol to include IL-18, IL-1β, TNF-α, IL-6, IL-4, IL-10, IL-8, or IL-2 in order to more easily study inflammasome activation and the resulting inflammatory cytokine cascade in inflammasome implicated diseases.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 7-12, 16, and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-39, and 56 of copending Application No. 17/255,653 in view of Wang et al. (US 2011/0082203 A1; Published: April 7, 2011), Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004), Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004), Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010), and Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995).
Claims 1, 3, 7-12, 16 and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-13, 17-19, and 21 of copending Application No. 18/464,174 in view of Wang et al. (US 2011/0082203 A1; Published: April 7, 2011), Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004), Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004), Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010), and Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995).
Regarding instant claims 9, 10, 21, and 22, copending claims 37-39, and 56 Application No. 17/255,653 teach treating inflammasome-related inflammation with an anti-ASC antibody comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31. The copending SEQ ID NOs and instant SEQ ID NOs with the same numeric identifier are 100% identical.
Regarding instant claims 9, 10, 21, and 22, copending claims 1, 3-13, and 21 of Application No. 18/464,174 teach treating an inflammatory neurologic condition inflammation with an anti-ASC antibody comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31. The copending SEQ ID NOs and instant SEQ ID NOs with the same numeric identifier are 100% identical. Copending claims 17-19 of Application No. 18/464,174 teach that administering the anti-ASC antibody results in the inhibition of the inflammasome and reduced inflammation cytokine levels.
The copending claims teach treating inflammation, but do not teach measuring a cytokine and comparing to a cut-off value.
Regarding instant claim 1, Wang et al. teaches a similar method comprising measuring the level of biomarker in a biological sample and diagnosing a neurological condition, including brain injury, based on the ratio of the biomarker; see claims 1, 5 and 6. In paragraph 0006, Wang et al. teaches that this method can be used to determine severity, predict outcomes, and guide therapy. Wang et al. teaches that severe brain injury is distinguishable by a ratio of 2 comparing the measured level to a relative baseline level; see paragraphs 0012-0014. And the baseline level is the level of the biomarkers in the absence of the neurological condition or a normal reference range; see paragraphs 0061 and 0063. Similarly, the method of instant claims 16 and 18-22 comprises two steps: obtaining a biological sample and measuring the level of at least one biomarker (i.e. an inflammasome protein) in the sample, wherein a level outside of the cut-off value is indicative of the prognosis.
Regarding instant claim 11, Wang et al. teaches that biological samples include CSF, blood, plasma, serum, saliva and urine. While tissue samples may be used, Wang et al. discourages tissues samples as they are “invasive and traumatizing”; see paragraphs 0054-0056.
Regarding instant claim 12, Wang et al. teaches that the method of measuring biomarkers to diagnose TBI severity or predict a patients prognosis can also be measured to “guide therapy of the condition, as well as monitor subject responsiveness and recovery” and serve as a “surrogate marker of therapeutic interventions”; see paragraphs 0006-0007.
Wang et al. does not teach using inflammatory cytokines as biomarkers for diagnosing neurological conditions.
Regarding instant claims 16-18, Chiaretti et al. teaches that elevated IL-1β and IL-6 plasma and CSF levels were associated with more severe head injury and poor outcome; see page 188 right column. Regarding “within a week” in instant claim 16, Chiaretti et al. collected plasma and CSF samples and measured the level of IL-1β and IL-6 at 2 hours and 24 hours post-TBI; see ‘Cytokine determination’ section. Regarding instant claim 19, the patients assessed were aged 3 months to 16 years; see ‘Study population […]’ section. Regarding the cut-off level of instant claim 16, Chiaretti et al. provides the IL-1β and IL-6 levels stratified by GCS>3 and GCS≤3 (poor outcome) at the 2-hour and 24-hour post-TBI collection; see Figure 5.
Chiaretti et al. does not teach inflammatory cytokine trends in adult patients with TBI.
Regarding instant claim 3, similar to Chiaretti et al., Hayakata et al. teaches that in adults with TBI, the level of inflammatory cytokine changes over time post-injury and differs depending on the biological sample assayed: see Figure 2. Additionally, Hayakata et al. teaches that the peak level of inflammatory cytokines can be associated with severe TBI and outcome; see Table 3.
Neither the copending claims, Wang et al., Chiaretti et al., nor Hayakata et al. teach the small molecules of instant claims 8 and 10.
Fang et al. teaches that propofol is the most common sedative agent used for patients with TBI; see page 5 left column. Additionally, Tang et al. teaches that propofol suppresses the secretion of IL-1β, IL-6, and TNF-α; see Abstract.
As evidenced by Orser et al. propofol functions as a glutamate receptor antagonist or NMDA receptor antagonist; see Abstract.
Regarding instant claims 1, 3-7, and 11, given that Wang et al. teaches a method of measuring a biomarker, comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury, and administering a therapeutic to alter the ratio of biomarker and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and suggests that measuring plasma and CSF interleukin amounts could identify the subset of patients having more pronounced neuroinflammation and who would benefit from glucocorticoids or other anti-inflammatory therapies (see page 191), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample, determine that the amount of IL-1β or IL-6 exceeds the cut-off value, and administer an agent which alters (i.e. increases or decreases) the amount of IL-1β or IL-6.
Further, regarding the cut-off values recited in instant claim 7, Chiaretti et al. and Hayakata et al. each demonstrate that inflammatory cytokine levels are dynamic (i.e. changing over time post-injury) and differ depending on the biological sample. It would have been obvious to one of ordinary skill in the art to determine the cut-off value for IL-1β and IL-6 in adult and pediatric patients with TBI for a given biological sample at a particular time post-injury. Indeed, Wang et al. provides guidance for determining the cut-off value correlated to severity of TBI; see paragraphs 0060-0062. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Regarding instant claims 8, 10, 20, and 22, given that propofol is the most common sedative administered to TBI patients, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer propofol to a patient with TBI. As evidenced by Orser et al. and Tang et al., propofol is a composition which decreases the amount of inflammatory cytokine and functions as a glutamate or NMDA receptor antagonist.
Regarding instant claims 9, 10, 21, and 22, because the copending claims of Application Nos. 17/255,653 and 18/464,174 teach treating inflammasome-related inflammation or inflammatory neurologic conditions and Chiaretti et al. and Hayakata et al. demonstrate that TBI results in inflammasome-related inflammation and is an inflammatory neurologic condition, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating TBI with the anti-ASC antibody taught by the copending claims of Application Nos. 17/255,653 and 18/464,174.
Because both propofol and the anti-ASC antibodies are taught by the copending claims and Tang et al. to reduce the level of inflammatory cytokine, it would have been obvious to one of ordinary skill in the art to administer both propofol and the anti-ASC antibody taught by the copending claims for the treatment of TBI. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Moreover, regarding instant claim 12, given that Wang et al. teaches that the method of measuring the biomarker can be used to monitor treatment response and administering a therapeutic which alters the biomarker ratio and Chiaretti et al. teaches treating the subset of patients with pronounced neuroinflammation with glucocorticoids or other anti-inflammatory therapies (which reduce the amount of inflammatory cytokines), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample following treatment for TBI, wherein a reduction in the amount of IL-1β or IL-6 is indicative of a positive treatment response.
Regarding instant claims 16-19, given that Wang et al. teaches a method of measuring a biomarker and comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and poor outcomes, it would have been obvious and one would have had a reasonable expectation of success to use the interleukin levels from the data provided in Figure 5 to create a cut-off value using the upper threshold of patients having GOS>3 outcomes to compare to plasma and CSF levels in other TBI patients, wherein a level less than the upper threshold or cut-off value is predictive of favorable outcome.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 7-12, 16, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 6 of U.S. Patent No. 10,703,811 B2 in view of Wang et al. (US 2011/0082203 A1; Published: April 7, 2011), Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004), Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004), Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010), and Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995).
Regarding instant claims 9, 10, 21, and 22, issued claims 1, 2, and 6 teach an anti-ASC antibody comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31 and a pharmaceutical composition comprising the anti-ASC antibody. The copending SEQ ID NOs and instant SEQ ID NOs with the same numeric identifier are 100% identical.
The issued claims do not teach measuring a cytokine and comparing to a cut-off value.
Regarding instant claim 1, Wang et al. teaches a similar method comprising measuring the level of biomarker in a biological sample and diagnosing a neurological condition, including brain injury, based on the ratio of the biomarker; see claims 1, 5 and 6. In paragraph 0006, Wang et al. teaches that this method can be used to determine severity, predict outcomes, and guide therapy. Wang et al. teaches that severe brain injury is distinguishable by a ratio of 2 comparing the measured level to a relative baseline level; see paragraphs 0012-0014. And the baseline level is the level of the biomarkers in the absence of the neurological condition or a normal reference range; see paragraphs 0061 and 0063. Similarly, the method of instant claims 16, 18, and 19 comprises two steps: obtaining a biological sample and measuring the level of at least one biomarker (i.e. an inflammasome protein) in the sample, wherein a level outside of the cut-off value is indicative of the prognosis.
Regarding instant claim 11, Wang et al. teaches that biological samples include CSF, blood, plasma, serum, saliva and urine. While tissue samples may be used, Wang et al. discourages tissues samples as they are “invasive and traumatizing”; see paragraphs 0054-0056.
Regarding instant claim 12, Wang et al. teaches that the method of measuring biomarkers to diagnose TBI severity or predict a patients prognosis can also be measured to “guide therapy of the condition, as well as monitor subject responsiveness and recovery” and serve as a “surrogate marker of therapeutic interventions”; see paragraphs 0006-0007.
Wang et al. does not teach using inflammatory cytokines as biomarkers for diagnosing neurological conditions.
Regarding instant claims 16 and 18, Chiaretti et al. teaches that elevated IL-1β and IL-6 plasma and CSF levels were associated with more severe head injury and poor outcome; see page 188 right column. Regarding “within a week” in instant claim 16, Chiaretti et al. collected plasma and CSF samples and measured the level of IL-1β and IL-6 at 2 hours and 24 hours post-TBI; see ‘Cytokine determination’ section. Regarding instant claim 19, the patients assessed were aged 3 months to 16 years; see ‘Study population […]’ section. Regarding the cut-off level of instant claim 16, Chiaretti et al. provides the IL-1β and IL-6 levels stratified by GCS>3 and GCS≤3 (poor outcome) at the 2-hour and 24-hour post-TBI collection; see Figure 5.
Chiaretti et al. does not teach inflammatory cytokine trends in adult patients with TBI.
Regarding instant claim 3, similar to Chiaretti et al., Hayakata et al. teaches that in adults with TBI, the level of inflammatory cytokine changes over time post-injury and differs depending on the biological sample assayed: see Figure 2. Additionally, Hayakata et al. teaches that the peak level of inflammatory cytokines can be associated with severe TBI and outcome; see Table 3.
Neither the copending claims, Wang et al., Chiaretti et al., nor Hayakata et al. teach the small molecules of instant claims 8, 10, 20, and 22.
Fang et al. teaches that propofol is the most common sedative agent used for patients with TBI; see page 5 left column. Additionally, Tang et al. teaches that propofol suppresses the secretion of IL-1β, IL-6, and TNF-α; see Abstract.
As evidenced by Orser et al. propofol functions as a glutamate receptor antagonist or NMDA receptor antagonist; see Abstract.
Regarding instant claims 1, 3, 7, and 11, given that Wang et al. teaches a method of measuring a biomarker, comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury, and administering a therapeutic to alter the ratio of biomarker and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and suggests that measuring plasma and CSF interleukin amounts could identify the subset of patients having more pronounced neuroinflammation and who would benefit from glucocorticoids or other anti-inflammatory therapies (see page 191), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample, determine that the amount of IL-1β or IL-6 exceeds the cut-off value, and administer an agent which alters (i.e. increases or decreases) the amount of IL-1β or IL-6.
Further, regarding the cut-off values recited in instant claim 7, Chiaretti et al. and Hayakata et al. each demonstrate that inflammatory cytokine levels are dynamic (i.e. changing over time post-injury) and differ depending on the biological sample. It would have been obvious to one of ordinary skill in the art to determine the cut-off value for IL-1β and IL-6 in adult and pediatric patients with TBI for a given biological sample at a particular time post-injury. Indeed, Wang et al. provides guidance for determining the cut-off value correlated to severity of TBI; see paragraphs 0060-0062. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Regarding instant claims 8, 10, 20, and 22, given that propofol is the most common sedative administered to TBI patients, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer propofol to a patient with TBI. As evidenced by Orser et al. and Tang et al., propofol is a composition which decreases the amount of inflammatory cytokine and functions as a glutamate or NMDA receptor antagonist.
Regarding instant claims 9, 10, 21, and 22, because U.S. Patent No. 10,703,811 B2 teaches treating TBI with the anti-ASC antibody of the issued claims (see column 3), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating TBI with the anti-ASC antibody taught by the issued claims of U.S. Patent No. 10,703,811 B2.
Because both propofol and the anti-ASC antibodies are taught by the issued claims and Tang et al. to reduce the level of inflammatory cytokine and be used for the treatment of TBI (see Background of U.S. Patent No. 10,703,811 B2), it would have been obvious to one of ordinary skill in the art to administer both propofol and the anti-ASC antibody taught by the copending claims for the treatment of TBI. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Moreover, regarding instant claim 12, given that Wang et al. teaches that the method of measuring the biomarker can be used to monitor treatment response and administering a therapeutic which alters the biomarker ratio and Chiaretti et al. teaches treating the subset of patients with pronounced neuroinflammation with glucocorticoids or other anti-inflammatory therapies (which reduce the amount of inflammatory cytokines), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample following treatment for TBI, wherein a reduction in the amount of IL-1β or IL-6 is indicative of a positive treatment response.
Regarding instant claims 16, 18, and 19, given that Wang et al. teaches a method of measuring a biomarker and comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and poor outcomes, it would have been obvious and one would have had a reasonable expectation of success to use the interleukin levels from the data provided in Figure 5 to create a cut-off value using the upper threshold of patients having GOS>3 outcomes to compare to plasma and CSF levels in other TBI patients, wherein a level less than the upper threshold or cut-off value is predictive of favorable outcome.
Claims 1, 3, 7-12, 16, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 7, and 13 of U.S. Patent No. 8,685,400 B2 in view of Wang et al. (US 2011/0082203 A1; Published: April 7, 2011), Chiaretti et al. (Childs Nervous System. 21: 185-193; Published: September 29, 2004), Hayakata et al. (Shock. 22(2): 102-107; Published: August 2004), Fang et al. (Neurosurgical Focus. 28(5): E11; Published: May 2010), Tang et al. (PLoS One. 6(12): e27890; Published: December 2, 2011), and Keane et al. (WO 2020/010273 A1; Published: January 09, 2020) and as evidenced by Orser et al. (British Journal of Pharmacology. 161: 1761-1768; Published: 1995).
Regarding instant claims 9, 10, 21, and 22, issued claims 1, 2, 6, 7, and 13 teach treating TBI comprising administering an antibody which binds an inflammasome component, including ASC.
The issued claims do not teach the structure of the anti-ASC antibody.
Keane et al. teaches anti-ASC antibodies comprising SEQ ID NOs: 6, 7, 8, 12, 13, and 14 or comprising one of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31; see Table 2 and claims 2-27. Further, Keane et al. teaches that the anti-ASC antibodies are used in methods of treating TBI and reduce the level of inflammatory cytokine; see claims 37-41 and Figure 8.
Keane et al. does not teach measuring a cytokine and comparing to a cut-off value.
Regarding instant claim 1, Wang et al. teaches a similar method comprising measuring the level of biomarker in a biological sample and diagnosing a neurological condition, including brain injury, based on the ratio of the biomarker; see claims 1, 5 and 6. In paragraph 0006, Wang et al. teaches that this method can be used to determine severity, predict outcomes, and guide therapy. Wang et al. teaches that severe brain injury is distinguishable by a ratio of 2 comparing the measured level to a relative baseline level; see paragraphs 0012-0014. And the baseline level is the level of the biomarkers in the absence of the neurological condition or a normal reference range; see paragraphs 0061 and 0063. Similarly, the method of instant claims 16, 18, and 19 comprises two steps: obtaining a biological sample and measuring the level of at least one biomarker (i.e. an inflammasome protein) in the sample, wherein a level outside of the cut-off value is indicative of the prognosis.
Regarding instant claim 11, Wang et al. teaches that biological samples include CSF, blood, plasma, serum, saliva and urine. While tissue samples may be used, Wang et al. discourages tissues samples as they are “invasive and traumatizing”; see paragraphs 0054-0056.
Regarding instant claim 12, Wang et al. teaches that the method of measuring biomarkers to diagnose TBI severity or predict a patients prognosis can also be measured to “guide therapy of the condition, as well as monitor subject responsiveness and recovery” and serve as a “surrogate marker of therapeutic interventions”; see paragraphs 0006-0007.
Wang et al. does not teach using inflammatory cytokines as biomarkers for diagnosing neurological conditions.
Regarding instant claims 16 and 18, Chiaretti et al. teaches that elevated IL-1β and IL-6 plasma and CSF levels were associated with more severe head injury and poor outcome; see page 188 right column. Regarding “within a week” in instant claim 16, Chiaretti et al. collected plasma and CSF samples and measured the level of IL-1β and IL-6 at 2 hours and 24 hours post-TBI; see ‘Cytokine determination’ section. Regarding instant claim 19, the patients assessed were aged 3 months to 16 years; see ‘Study population […]’ section. Regarding the cut-off level of instant claim 16, Chiaretti et al. provides the IL-1β and IL-6 levels stratified by GCS>3 and GCS≤3 (poor outcome) at the 2-hour and 24-hour post-TBI collection; see Figure 5.
Chiaretti et al. does not teach inflammatory cytokine trends in adult patients with TBI.
Regarding instant claim 3, similar to Chiaretti et al., Hayakata et al. teaches that in adults with TBI, the level of inflammatory cytokine changes over time post-injury and differs depending on the biological sample assayed: see Figure 2. Additionally, Hayakata et al. teaches that the peak level of inflammatory cytokines can be associated with severe TBI and outcome; see Table 3.
Neither the copending claims, Wang et al., Chiaretti et al., nor Hayakata et al. teach the small molecules of instant claims 8 and 10.
Fang et al. teaches that propofol is the most common sedative agent used for patients with TBI; see page 5 left column. Additionally, Tang et al. teaches that propofol suppresses the secretion of IL-1β, IL-6, and TNF-α; see Abstract.
As evidenced by Orser et al. propofol functions as a glutamate receptor antagonist or NMDA receptor antagonist; see Abstract.
Regarding instant claims 1, 3, 7, and 11, given that Wang et al. teaches a method of measuring a biomarker, comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury, and administering a therapeutic to alter the ratio of biomarker and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and suggests that measuring plasma and CSF interleukin amounts could identify the subset of patients having more pronounced neuroinflammation and who would benefit from glucocorticoids or other anti-inflammatory therapies (see page 191), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample, determine that the amount of IL-1β or IL-6 exceeds the cut-off value, and administer an agent which alters (i.e. increases or decreases) the amount of IL-1β or IL-6.
Further, regarding the cut-off values recited in instant claim 7, Chiaretti et al. and Hayakata et al. each demonstrate that inflammatory cytokine levels are dynamic (i.e. changing over time post-injury) and differ depending on the biological sample. It would have been obvious to one of ordinary skill in the art to determine the cut-off value for IL-1β and IL-6 in adult and pediatric patients with TBI for a given biological sample at a particular time post-injury. Indeed, Wang et al. provides guidance for determining the cut-off value correlated to severity of TBI; see paragraphs 0060-0062. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
Regarding instant claims 8, 10, 20, and 22, given that propofol is the most common sedative administered to TBI patients, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer propofol to a patient with TBI. As evidenced by Orser et al. and Tang et al., propofol is a composition which decreases the amount of inflammatory cytokine and functions as a glutamate or NMDA receptor antagonist.
Regarding instant claims 9, 10, 21, and 22, because U.S. Patent No. 8,685,400 B2 teaches treating TBI with an antibody which binds an inflammasome component and Keane et al. teaches an anti-ASC antibody which can be used to treat TBI, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating TBI with the anti-ASC antibody taught by the issued claims of U.S. Patent No. 8,685,400 B2 and Keane et al..
Because both propofol and the anti-ASC antibodies are taught by the issued claims and Tang et al. to reduce the level of inflammatory cytokine and be used for the treatment of TBI, it would have been obvious to one of ordinary skill in the art to administer both propofol and the anti-ASC antibody taught by the copending claims for the treatment of TBI. Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Moreover, regarding instant claim 12, given that Wang et al. teaches that the method of measuring the biomarker can be used to monitor treatment response and administering a therapeutic which alters the biomarker ratio and Chiaretti et al. teaches treating the subset of patients with pronounced neuroinflammation with glucocorticoids or other anti-inflammatory therapies (which reduce the amount of inflammatory cytokines), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to measure IL-1β and IL-6 in a biological sample following treatment for TBI, wherein a reduction in the amount of IL-1β or IL-6 is indicative of a positive treatment response.
Regarding instant claims 16, 18, and 19, given that Wang et al. teaches a method of measuring a biomarker and comparing to a ratio relative to a normal reference range in order to diagnose severe traumatic brain injury and Chiaretti et al. teaches that elevated IL-1β and IL-6 in the plasma and CSF at 2 hours and 24 hours following a TBI are associated with severe injury and poor outcomes, it would have been obvious and one would have had a reasonable expectation of success to use the interleukin levels from the data provided in Figure 5 to create a cut-off value using the upper threshold of patients having GOS>3 outcomes to compare to plasma and CSF levels in other TBI patients, wherein a level less than the upper threshold or cut-off value is predictive of favorable outcome.
Response to Arguments
Applicant’s amendments filed July 9, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant's arguments filed July 9, 2026 have been fully considered but they are not persuasive.
Regarding the rejection under 35 U.S.C. 101, Applicant argues that the claims are directed to a biomarker-guided treatment of TBI and that claims integrate the judicial exception because they recite a “concrete treatment protocol”.
Independent claims 1 and 16 as amended now recite a method where the treatment of a composition selected to inactivate or neutralize the measure inflammatory cytokine or inflammasome protein is only administered when the patient is outside of the cut-off value. The method then encompasses scenarios where the patient is not outside of the cut-off-value and, therefore, does not receive a composition selected to inactivate or neutralize the measure inflammatory cytokine or inflammasome protein. Further, Applicant argues that concrete treatment protocol, which is interpreted to mean that Applicant considers this treatment protocol to be definite or specific. Specificity, however, is the issue – claims 1 and 16 do not recite a particular treatment, but rather anything that might “inactivate or neutralize” the measured cytokine or inflammasome protein. It is unclear if the measured cytokine or inflammasome protein need be the one “outside” of the cut-off value.
Applicant argues that the Office considered the treatments recited in subsequent dependent claims to not be particular treatments. The small molecules are particular treatments. The issue of particular treatments in the context of dependent claims is with the sequences of the antibodies recited. As stated in the rejection under 35 U.S.C. 112(a), these sequences are not enabled because they do not recite the minimum structures needed to function in inactivating or neutralizing the cytokine or inflammasome protein as claimed. For example, SEQ ID NO: 6 is one CDR, where an antibody, with the rare exception of single domain antibodies, requires six CDRs.
Regarding the rejection under 35 U.S.C. 112(b), the previous rejections of record, except over claim 10, are resolved by amendment and new rejections set forth; see above.
Regarding the rejection under 35 U.S.C. 112(a), the rejection is maintained. Recitation of the amino acid sequences as follows would be enabled: wherein said composition comprises an antibody or fragment thereof which comprises either: 1. SEQ ID NOs: 6, 7, 8, 12, 13, and 14, or 2. One of SEQ ID NOs: 18-22 and one of SEQ ID NOs: 28-31.
Regarding the rejection under 35 U.S.C. 112(d), the previous rejections of record are resolved by amendment.
Regarding the rejection under 35 U.S.C. 102, Applicant argues that claim 13 now requires labeled binding partners for all inflammatory cytokines and inflammasome proteins. The amendments render claim 13 indefinite; see above. However, the claim is interpreted as requiring a binding partner for each of the recited cytokines (i.e. the interleukins and TNF-alpha) or inflammasome proteins (i.e. caspase-1 and ASC). The reference no longer anticipates.
Regarding the rejections under 35 U.S.C. 103, Applicant argues improper hindsight.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, both Wang et al. and Chiaretti et al. teach the use of biomarkers for diagnosing and predicting outcomes in TBI and Chiaretti et al. teaches inflammatory markers as biomarkers for TBI severity and clinical outcome. One would have been motivated by the common use. Additionally, Wang et al. teaches about the need for inexpensive and rapid diagnostics as a counter to diagnostic imagine in TBI; see paragraphs 0005-0006. Chiaretti et al. demonstrates that assessing IL-1beta and IL-6 is a rapid alternative to diagnostic imaging.
Applicant argues that neither Wang et al. nor Chiaretti et al. teach predetermined cut-off values. Wang et al. teaches baseline or reference levels of biomarker and using a fold change in each biomarker to diagnose TBI and predict outcomes. This baseline or reference level is associated with the absence of TBI and is not a before value for a particular individual. Chiaretti et al. teaches the levels of inflammatory cytokines associated with severe TBI and healthy controls. As above, it would have been obvious to make predetermined cut-off values given the teaching of Wang et al. and to make these predetermined cut-off values for the inflammatory cytokines taught by Chiaretti et al.
Applicant argues that neither Wang et al. nor Chiaretti et al. teach administering a therapeutic effective to alter the measured cytokine concentration toward a normal reference value. Wang et al. teaches treating TBI by administering to alter the ratio of one or more biomarkers; see paragraph 0012 for example. Chiaretti et al. teaches that in TBI, IL-1beta and IL-6 are elevated compared to health controls. Chiaretti et al. teaches the use of IL-18 binding protein (a specific IL-18 inhibitor) has been associated with improved recovery in animal models with experimental TBI. Taken together, Wang et al. and Chiaretti et al. teach administering a therapeutic to alter the cytokine concentration to a normal reference value.
Applicant argues that neither Wang et al. nor Chiaretti et al. teach prognosis based upon a predetermined threshold. As discussed above, both Wang et al. and Chiaretti et al. teach utilizing biomarkers to determine prognostic outcome. Chiaretti et al. stratifies the levels of IL-1beta and IL-6 in TBI patients by outcome effectively providing a value from which one could predict outcomes.
The rejections under 35 U.S.C. 103 are maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Adamczak et al. (Journal of Neurosurgery. 117(6): 1119-1125; Published Online: October 12, 2012) teaches that higher levels of the inflammasome proteins ASC, caspase-1, and NALP-1 (a.k.a. NLRP1) are associated with more severe TBI and unfavorable outcome at 5 months post-injury. Utagawa et al. (Experimental Neurology. 211: 283-291; Published Online: February 6, 2008) teaches that IL-1β is associated with worse outcome in TBI.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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