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 .
Claim Interpretation
Claims 1-12 are drawn to the method of measuring “one or more inflammatory cytokine[s]” to assess and treat traumatic brain injury. Inflammatory cytokines are interpreted as secreted proteins acting as chemical messengers to regulate inflammation. Inflammatory cytokines encompasses both pro-inflammatory cytokines and anti-inflammatory cytokines.
Claims 16-19 are drawn to the method of determining prognosis of a patient with traumatic brain injury comprising measuring “at least one inflammasome protein”. Paragraph 0039 of the instant disclosure defines an "inflammasome protein" as “a protein component of inflammasome complexes and can include, but is not limited to, a nucleotide binding domain, leucine-rich repeat containing (NLR) family member (e.g., NLRP1), ASC, caspase-1, caspase-11 X-linked inhibitor of apoptosis protein (XTAP), and pannexin-1.”
Generally, inflammatory cytokines and inflammasome proteins would be considered two distinct categories of proteins. However, there is some ambiguity regarding whether the inflammatory cytokines IL-1β and IL-18 are also inflammasome proteins. IL-1β and IL-18 are cleaved by caspase-1 into their active forms. Caspase-1 complexes with the leucine-rich repeat containing (NLR) family member (e.g., NLRP1) and ASC to form the inflammasome complex by which caspase-1 becomes activated. There are two competing theories regarding whether caspase-1 is active in complex or out of complex. The longstanding theory has been that once in complex, caspase-1 becomes cleaved and liberated from the inflammasome complex into its active form. Alternatively, there is an emerging theory that caspase-1 is active when in complex and that cleavage of caspase-1 results in its inactivation. The figure below from Makoni et al. (Arch Biochem Biophys. 699: 108753; Published: January 13, 2021) depicts the two theories of caspase-1 activation.
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These two theories of caspase-1 activation are significant for IL-1β and IL-18 because if the alternative theory (i.e. caspase-1 is only active in complex) is true, then IL-1β and IL-18 are inflammasome proteins by the instant definition, as well as inflammatory cytokines.
Because U.S. Provisional Application 63/016,033 teaches the measuring of “inflammasome proteins” and demonstrates measurements IL-1β and IL-18, “inflammasome proteins” is interpreted to include IL-1β and IL-18 which are also inflammatory cytokines.
Priority
Claims 1-12 are drawn to the method of measuring “one or more inflammatory cytokine[s]”. The measurement of inflammatory cytokines, specifically IL-1β and IL-18, are not disclosed until U.S. Provisional Application 63/016,033 filed April 27, 2020. Claims 5-7 refer to a group of 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. Claims 9 and 10 recite antibodies and antibody fragments comprising SEQ ID NOs: 1-41. SEQ ID NOs: 5-41 are not disclosed until U.S. Provisional Application 63/062,622 filed August 7, 2020.
Thus, claims 1-4, 8, 11, and 12 are examined with the effective filing date of April 27, 2020, claims 5-7 are examined with the effective filing date of April 25, 2022, and claims 9 and 10 are examined with the effective filing date of August 7, 2020.
Claims 13-15 recite a kit for measuring the same cytokines as recited in claims 5-7. These cytokines are not disclosed until U.S. Provisional Application 63/334,218 filed April 25, 2022.
Thus, claims 13-15 are examined with the effective filing date of April 25, 2022.
Claims 16-19 are drawn to the method of determining prognosis of a patient with traumatic brain injury comprising measuring “at least one inflammasome protein”. Support for measuring inflammasome proteins, specifically ASC and caspase-1, is found in U.S. Provisional Application 61/595,254 filed February 6, 2012. Claim 17 recites the cytokines also recited in claims 5-7. These cytokines are not disclosed until U.S. Provisional Application 63/334,218 filed April 25, 2022.
Thus, claims 16, 18, and 19 are examined with the effective filing date of February 6, 2012 and claim 17 is examined with the effective filing date of April 25, 2022.
Should Applicant disagree with the analysis above, he/she must point to the precise location within a specific document in the domestic priority chain wherein the subject matter is disclosed.
Claim Objections
Claims 1, 8-10, and 13 are objected to because of the following informalities:
In claims 1 and 16, “providing” suggests one is giving something, but in the method of claim 1, one performing the method is the recipient of a biological or tissue sample. The word “obtaining” would be more appropriate.
In claim 1, the word “cytokine” in line 4 should be “cytokines” and the word “patient” in line 4 should be either deleted or replaced with “patient’s”.
In claims 8 and 10, “one or more small molecule” should be “one or more small molecules”.
In claims 9 and 10, “one or more antibody or antibody fragment” should be “one or more antibodies or antibody fragments”.
In claim 13, the intended use of the kit is to prepare an inflammatory cytokine profile. Since claim 13 recites more than inflammatory cytokines (i.e. caspase-1 and ASC), it may be more appropriate to recite preparing an inflammatory cytokine or inflammasome protein profile.
Appropriate correction is required.
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 1-12 and 16-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomenon without significantly more.
Claims 1-12 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 all patients are administered the composition regardless of cytokine levels. Moreover, the compositions recited in claims 1 and 2 are 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 16-19 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 there is no step following the step of measuring where the level of inflammasome protein is used to guide further treatment. 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 1-19 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 the limitation "said inflammatory protein" in line 6. There is insufficient antecedent basis for this limitation in the claim. Line 4 recites "one or more inflammatory cytokine[s]", but there is not recitation of an inflammasome protein. It is unclear whether the claim is limited to measuring inflammatory cytokines and comparing the level to a cut-off value or if the claim, perhaps more broadly, encompasses measuring “inflammatory proteins”. If the latter, it is unclear what “inflammatory proteins” encompasses as this is not a common phrase in the art and is not defined in the instant Specification. One might reason that “inflammatory proteins” encompasses any protein, not limited to cytokines, which increase in injury or infection. However, one cannot immediately envisage all members of this genus. For the purpure of compact prosecution and because “inflammatory proteins” only appears once in claims 1-12, "said inflammatory protein" in line 6 is interpreted to mean “inflammatory cytokine”.
Claim 1 recites said inflammatory protein, interpreted to mean cytokine, “meets a pre-determined cut-off value”. It is unclear what is meant by “meets”. Additionally, it is unclear how a protein “meets,” which conveys a physical or temporal connection, a value. Does this mean that the amount of an inflammatory cytokine is equal to a cut-off value? If it is greater or less than, does that “meet” the cut-off value? For the purpose of compact prosecution, cut-off value is interpreted as a threshold value of which amounts of inflammatory cytokine greater than or less than, depending on the cytokine indicated traumatic brain injury.
Claim 1 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. Then, claim 2, which depends from claim 1, recites that the composition is “active against the inflammatory cytokine such that the inflammatory cytokine is inactivated or neutralized”. It is unclear if “active against” means that the small molecule or antibody or antibody fragment thereof binds to the inflammatory cytokine. Claims 1 and 2 conflict and it is unclear whether the composition inactivates or neutralizes the amount of inflammatory cytokine or the inflammatory cytokine itself. For the purpose of compact prosecution, the composition of claim 1 is interpreted as decreasing or increasing the amount of inflammatory cytokine and the composition of claim 2 is interpreted as a small molecule or antibody or antibody fragment which both inactivates or neutralizes (i.e. directly binds and inhibits) an inflammatory cytokine and reduces or increases the amount of an inflammatory cytokine.
Claim 12 recites the limitation "neuroprotective treatment" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether the composition of claim 1 is the neuroprotective treatment. For the purpose of compact prosecution, the neuroprotective treatment of claim 12 is interpreted as being the same as the composition of claim 1.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “inflammatory cytokine” in claims 5-7 is used by the claim to mean “caspase-1, ASC, IL-18, TNF-α, IL-6, IL-4, IL-10, IL-8, IL-2, and IL-1β,” while the accepted meaning is low molecular weight, secreted signaling proteins which regulate inflammation. Neither caspase-1 nor ASC are known to be secreted . While caspase-1 and ASC can be found extracellularly, they released via pyroptosis – not secretion. Additionally, neither caspase-1 nor ASC are known to function as signaling proteins – they are not known to be cytokines. The term is indefinite because the specification does not clearly redefine the term. Similarly, claim 17 recites “inflammatory cytokine” followed by a grouping which includes caspase-1 and ASC.
Likewise, claims 13 and 14 recite a kit comprising a labeled-binding partner which binds to one or more “inflammasome proteins”. Paragraph 0039 of the instant disclosure defines an "inflammasome protein" as “a protein component of inflammasome complexes and can include, but is not limited to, a nucleotide binding domain, leucine-rich repeat containing (NLR) family member (e.g., NLRP1), ASC, caspase-1, caspase-11 X-linked inhibitor of apoptosis protein (XTAP), and pannexin-1.” TNF-α, IL-6, IL-4, IL-10, IL-8, and IL-2 are recited in the claim as included in the group of inflammasome proteins. These cytokines are not known to complex with the inflammasome, and thus, the inclusion of these cytokines in the group of inflammasome proteins makes unclear where the metes and bounds of inflammasome proteins lies. For the purpose of compact prosecution, the claim is interpreted as reciting a kit of labeled-binding partners that bind to one or more inflammasome proteins or inflammatory cytokines.
Examiner suggests reciting “inflammasome protein or inflammatory cytokine” in place of “inflammasome protein”, “inflammatory protein”, or “inflammatory cytokine” recited alone. The combination of “inflammasome protein or inflammatory cytokine” in the alternative would encompass the proteins recited in claims 5-7, 13, 14, and 17.
Additionally, claim 14 recites that the kit comprises a label antibodyor fragment thereof. It is unclear if the labeled antibody or fragment thereof in claim 14 is the labeled binding partner of claim 13. For the purpose of compact prosecution, the labeled antibody or fragment thereof of claim 14 is interpreted as further limiting the labeled binding partner of claim 13.
Claim 15 recites the limitation "the labeled antibody or fragment thereof, aptamer, or peptide". There is insufficient antecedent basis for this limitation in the claim. Further, claim 15 contains no verbs – it is unclear what is being claimed because claim 15 is not a complete sentence. For the purpose of compact prosecution, claim 15 is interpreted as reciting “wherein the labeled binding partner is a labeled antibody or fragment thereof, aptamer, or peptide.”
Claims 6 and 7 recite wherein the cut-off value is + or – 20% of a subsequent table of cut-off values. The term cut-off value suggests a single value where the determination is made based on whether the measurement value falls above or below that single value. This is interpretation is supported by the greater than or less than symbols associated with the cut-off value for each protein. For example, in claim 6, the cut-off value for caspase-1 is greater than 0.8150 pg/ml. + or – 20% of 0.8150 pg/ml is 0.652 pg/ml and 0.978 pg/ml. It is unclear whether the treatment step of claim 1 is only done if the caspase-1 is greater than 0.8150, 0.652, or 0.978 pg/ml. For the purpose of compact prosecution, claims 6 and 7 are interpreted as administering the composition when the level is greater than or less than the single value listed in the table for each protein.
Claim 16 recites “measuring the level of at least one inflammasome protein […] to prepare an inflammatory cytokine prolife”. With the exception of IL-1β and IL-18, inflammasome proteins and inflammatory cytokines are understood to denote two distinct groupings of proteins. It is unclear whether the claim encompasses only measuring IL-1β and IL-18. For the purpose of compact prosecution, the claim is interpreted as measuring inflammasome proteins to prepare an inflammasome protein profile.
Claim 9 recites both a parenthetical and exemplary language in the limitation “other glutamate receptor antagonists (e.g., NMDA receptor antagonists)”. “E.g.” meaning ‘for example’ and the parenthesis each make unclear whether the “other glutamate receptor antagonists” are required to be NMDA receptor antagonists. For the purpose of compact prosecution, glutamate receptor antagonists are not required to be NMDA receptor antagonists.
Additionally, claim 9 recites “one or more small molecule[s] selected from the group consisting of […] resveratrol, and other glutamate receptor antagonists (e.g., NMDA 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.
Claims 2-12, 14, 15, and 17-19 are rejected for depending from claims 1, 13, or 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 and 10 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: 1-41.
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 and 10, 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 § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5-10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 5-7 recites inflammatory cytokines and lists caspase-1 and ASC. Neither caspase-1 nor ASC are cytokines. Thus, claims 5-7 broaden the scope of claim 1 from which they ultimately depend.
Claims 9 and 10 recite treatments. Claim 1 is indefinite and interpreted as a composition which increases or decreases the amount of cytokine. Not all of the SEQ ID NOs in claims 9 and 10 inactivate or neutralize the cytokine.
Specifically, the SEQ ID NOs of claim 9 and 10 which are recited to be antibodies or fragments thereof are not all antibodies. SEQ ID NOs: 1-5 are epitopes of ASC or NLRP1 – not antibody sequences. SEQ ID NOs: 9-11, 15-17, 23-27, and 32-35 are nucleic acid sequences, of which antibodies or antibody fragments are not comprised. SEQ ID NOs: 36-40 are amyloid β or amyloid precursor proteins – not antibodies or antibody fragments. SEQ ID NO: 41 is NFL – not antibodies or antibody fragments. 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. The only antibody or antibody fragments encompassed in the claim are sequences taught in the disclosure of 17/921,600 to be associated with anti-ASC antibodies. ASC is an inflammasome protein – it is not known to be a cytokine – however, inhibiting the oligomerization the inflammasome via an anti-ASC antibody would decrease the amount of cytokine. Thus, the sequences recited broaden the scope of claim 1.
It is noted that the small molecules of claim 10 do reduce the amount of inflammatory cytokine; however, none are known to directly bind cytokines. Rather, methylprednisolone, 17α-estradiol, 17β-estradiol, ginsenoside (an antioxidant), progesterone, simvastatin, deprenyl, minocycline, resveratrol (an antioxidant), and glutamate or NMDA receptor antagonists inhibit NF-kB reducing the synthesis of inflammatory cytokines; see Ocejo et al. (Methylprednisolone. StatPearls; Published Online: August 11, 2024), Santos et al. (Biology of Sex Differences. 8:30; Published: September 6, 2017), Im, Dong-Soon. (Biomolecules. 10(3): 444; Published: March 13, 2020), Azeez et al. (American Journal of Cancer Research. 11(11): 5214-5232; Published: November 30, 2021), Lietzau et al. (Molecular Neurobiology. 60: 4935-4951; Published: May 19, 2023), Emanuel et al. (iScience. 25(5): 104207; Published: April 5, 2022), Guerra et al. (Stem Cell Research & Therapy. 8: 171; Published: July 21, 2017), Ren et al. (Pharmazie. 68(8): 689-694; Published: August 2013), and Shen et al. (Brain Research. 933(1): 23-30; Published: April 12, 2002).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 13 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the Milliplex Human Cytokine / Chemokine Magnetic Bead Panel Protocol (EMD Millipore Corporation; Published: May 24, 2017).
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. Claim 15 is interpreted as reciting that the labeled binding partner is a labeled antibody or fragment thereof, aptamer, or peptide.
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 15, 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.”
Thus, the kit taught by the protocol comprises specific antibodies labeled by fluorescent dye contained in a microsphere which specifically bind to at least one protein recited in claim 13 and anticipates claims 13 and 15.
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 14 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).
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.
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 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 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, 4, 5, 7, 11, 12, and 16-19 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).
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 16-19 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 16-18, 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 claims 4 and 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, 4, 5, 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 16-19, 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, 4, 5, 7, 11, 12, and 16-19 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, 4, 5, 7, 11, 12, and 16-19, 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.
Claims 3 and 6 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, 4, 5, 7, 11, 12, and 16-19 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, 4, 5, 7, 11, 12, and 16-19, 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.
Further, regarding the cut-off values recited in claim 6, 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 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).
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 8 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, 4, 5, 7, 11, 12, and 16-19 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, 4, 5, 7, 11, 12, and 16-19, 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 claim 8.
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.
Claim 9 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, 4, 5, 7, 11, 12, and 16-19 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, 4, 5, 7, 11, 12, and 16-19, 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 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.
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 10 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, 4, 5, 7, 11, 12, and 16-19 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, 4, 5, 7, 11, 12, and 16-19, 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 claim 10 in combination with an anti-ASC antibody comprising one or more of the SEQ ID NOs recited in claim 10.
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 claim 10.
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 and 15-19 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 claims 13 and 15, copending claims 20-23 teach a kit comprising labeled binding partners or antibodies which bind to caspase-1 and ASC.
Regarding instant claims 16-18, 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 and 15-19 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, 3-8, 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. Regarding instant claim 4, 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. Regarding claim 4, 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 claims 6 and 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, 3-8, 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, 3-8, 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, 3-8, 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, 3-8, 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 14 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, 3-12, and 16-19 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, 3-12, and 16-19 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 and 10, 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 and 10, 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 16-19 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 16-18, 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 claims 4 and 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 claims 6 and 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 and 10, 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 and 10, 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, 3-12, and 16-19 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 and 10, 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 16-19 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 16-18, 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 claims 4 and 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 claims 6 and 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 and 10, 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 and 10, 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 16-19, 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, 3-12, and 16-19 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 and 10, 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 16-19 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 16-18, 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 claims 4 and 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 claims 6 and 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 and 10, 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 and 10, 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 16-19, 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.
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.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682