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 .
Claims 1-46 are cancelled.
Applicant’s election without traverse of the following species:
1. A single option from either of independent claim 47 and its dependents (claims 48-62)
or independent claim 63 and its dependents (claims 64-66);
-Applicant elects claim 63 and its dependents (claims 64-66).
2. A single condition to treat from the list of sepsis, ARDS, or severe COVID-19 and
associated ARDS, as recited in optional step (b) of claim 47;
-Applicant elects severe COVID-19.
3. A single amino acid sequence from SEQ ID NO: 1-7, as recited in claim 48;
-Applicant elects SEQ ID NO: 7.
4. A single option of either SDF-1 or activators of SDF-1 as recited in claim 55;
-Applicant elects SDF-1.
5. A single option of one of the amino acids sequences of SEQ ID NO: 1-7, SerSDFI(S4V), or an analogue of one of SEQ ID NO: 1-7 or an analogue of Ser-SDFI(S4V) as recited in
claim 57;
-Applicant elects SEQ ID NO: 7.
6. A single SDF-1 small peptide from the group consisting of: CTCE-0214, CTCE-0324,
an analogue of CTCE-0214, an analogue of CTCE-0324, as recited in claim 58;
-Applicant elects CTCE-0324.
7. A single option from one of SEQ ID Nos: 1-7, Ser-SDFI(S4V), an analogue of SEQ ID
Nos: 1-7, or an analogue of Ser-SDFI(S4V), as recited in claim 59;
-Applicant elects SEQ ID NO: 7, as above in points 3 and 5.
8. A single option of a viral vector, a non-viral vector, a cell, a stem cell, a mesenchymal
stem cell, or microvesicles from cells as a carrier as recited in claim 59;
-Applicant elects "a non-viral vector."
9. One of dependent claims 56, 58, 59, 60, or 61 representing the agent to be administered after the method of claim 55 from which the enumerated dependent claims 56, 58, 59, 60, and 61 depend;
-Applicant elects recombinant SDF-1.
10. A single option of ARDS or severe COVID-19, as recited in claim 63;
-Applicant elects "severe COVID-19."
11. One of options (i)-(x), as recited in claim 65;
-Applicant elects (i) administering an antagonist of CXCR4.
12. A single PI3K inhibitor from the options recited in part (ii) of claim 65;
-No election is made because species (i) is elected above in genus 11.
13. A single option of one or more anti sense oligos that transiently inhibit expression of
CXCR4 or of one or more anti sense oligos that transiently inhibit expression of
P110gPI3K, as recited in part (iii) of claim 65;
-No election is made because species (i) is elected above in genus 11.
14. A single option of LEVD-fmk, Emriscan, an analogue of LEVD-fmk, or an analogue of Emriscan, as recited in part (v) of claim 65;
-No election is made because species (i) is elected above in genus 11.
15. From part (vi) of claim 65, a single option of:
a. An siRNA, shRNA, antisense oligo, CRISPR/guide RNA, or a genome editing
system; and
b. Which inhibits a single option from the group consisting of Caspase 4/5 or a
dominant negative Caspase 4/5 that inhibits Caspase 4/5 function;
-No election is made because species (i) is elected above in genus 11.
16. A single option of either GSDMD or GSDME, as recited in part (vii) of claim 65;
-No election is made because species (i) is elected above in genus 11.
17. From part (ix) of claim 65, a single option of:
a. An siRNA, shRNA, antisense oligo, CRISPR/guide RNA, or a genome editing
system;
b. Which inhibits a single option from the group consisting of GSDMD or
GSDME;
-No election is made because species (i) is elected above in genus 11.
18. One of a dominant negative GSDMD that inhibits GSDMD function, a dominant
negative GSDME that inhibits GSDME function, or both of a dominant negative
GSDMD that inhibits GSDMD function and a dominant negative GSDME that inhibits
GSDME function, as recited in part (x) of claim 65;
-No election is made because species (i) is elected above in genus 11.
19. A single option from parts i-iii of claim 66;
-Applicant elects (i): "administering to the subject an antagonist of C-X-C motif chemokine receptor 4 (CXCR4)," as recited in claim 66.
20. A single PI3K inhibitor from the alternatives recited in part ii of claim 66; and
-No election is made because species (i) is elected above in genus 19.
21. A single species from the group consisting of: an siRNA, an shrRNA, one or more anti-sense oligos that transiently inhibit expression of CXCR4, and one or more anti-sense oligos that transiently inhibit expression of p110gP13K, as recited in part iii of claim 66;
-No election is made because species (i) is elected above in genus 19,
in the reply filed on 04/30/2026 is acknowledged.
Claims 47-62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/30/2026.
Claims 47-66 are pending.
Claims 63-66 are under examination on the merits.
Priority
This application is a 371 of PCT/US21/73066, filed 12/22/2021, which claims benefit of US Provisional Application No. 63/129,544, filed 12/22/2020.
IDS
The information disclosure statement (IDS) filed 04/24/2024 has been considered.
Claim Interpretation
The specification never discusses or discloses treatment of Covid-19 or ‘severe’ covid-19 specifically. The specification does however discuss treatment of ARDs induced by Covid-19 (Covid-19-associated ARDS). Therefore, recitations of treating severe Covid-19 are being interpreted to mean treatment of ARDs-induced by Covid-19 in order to provide expedient examination of the claim scope supported by the instant specification.
The specification defines about at paragraph 0029 of page 11 as “…understood by persons of ordinary skill in the art and will vary to some extent on the context in
which they are used. If there are uses of the term which are not clear to persons of ordinary skill
in the art given the context in which it is used, "about" and "approximately" will mean up to plus
or minus 10% of the particular term and "substantially" and "significantly" will mean more than
plus or minus 10% of the particular term.” To provide clarity as to the metes and bounds of the claim scope, all recitation of about will be understood to mean +/- 10% of the modified value.
Claim 66 is being interpreted to mean that the treatment with the recited treatment (such as the CXCR4 antagonist) is not continued for more than 3 days in an effort to clarify the metes and bounds of the claim.
35 U.S.C. 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 63-66 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to mathematical concepts.
Claim 63 is directed to a method comprising administering treatment for acute respiratory distress syndrome (ARDS) or severe COVID-19 to a subject exhibiting a concentration of stromal cell- derived factor 1 (SDF1) protein in a blood, serum, or plasma sample from the subject at admission to ICU or early onset of ARDS that is equal to or higher than a reference concentration.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
YES-Claim 63 is directed to a method which is a process.
Step 2A – Prong I: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
YES- Claim 63 recites a subject exhibiting a concentration of stromal cell derived factor I (SDFI) protein in a blood, serum, or plasma sample from the subject at admission to ICU or early onset of ARDS that is equal to or higher than a reference concentration. Indeed this exhibiting of concentration is achieved by detecting the expression correlating a measured level of SDF1 with an implied need for treatment of ARDS or severe COVID-19 (a natural phenomenon). This correlation to expression of a level of SDF1 to acute respiratory distress syndrome (ARDS) or severe COVID-19 is a natural correlation. The claim language reciting the judicial exception is found throughout the entirety of the claim as drafted.
Step 2A – Prong II: Does the claim integrate the judicial exception into a practical application?
NO- Here, the instant claim 63 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition. No specific treatment administration step is recited.
Step 2B- Does the claim recite additional elements that amount to significantly more than the judicial exception?
NO-The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
The generic recitation of measuring a SDF1 level from a sample amounts to no more than mere data gathering steps and does not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited throughout the entirety of the claim.
64-66 incorporate, via dependency, the judicial exceptions recited in claim 1 and are therefore included in this rejection.
Claim 64 recites the method of claim 63, wherein the detected concentration and/or reference concentration is at least about 1 ng/ml, 2 ng/ml, 3 ng/ml, 4 ng/ml, 5 ng/ml, 6 ng/ml, 7 ng/ml, 8 ng/ml, 9 ng/ml, 10 ng/ml, 11 ng/ml, 12 ng/ml, 13 ng/ml, 14 ng/ml, 15 ng/ml, or higher. There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. No active steps are added by claim 64 so as to add significantly more.
Claim 65 recites the method of claim 63, wherein treating the subject comprises administering to the subject one member of alternatively recited genera (a CXCR4 antagonist being the elected species). There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The mere recitation of administering an unspecified CXCR4 antagonist (with no specified route of administration, doing regimen, time frame within the infection cycle etc) amounts to no more than a suggestion to apply the judicial exceptions of claim 1 (see MPEP §2106.05(f)). No further active steps are recited so as to add significantly more to the judicial exception.
Claim 66 recites The method of claim 65, wherein the subject is treated for no more than about 3 days when administering to the subject one member of alternatively recited genera (a CXCR4 antagonist being the elected species). There is no step that would integrate the claim, such as a particular treatment/prophylaxis step. The mere recitation of administering an unspecified CXCR4 antagonist for no more than 3 days (with no specified route of administration, doing regimen, time frame within the infection cycle etc) amounts to no more than a suggestion to apply the judicial exceptions of claim 1 (see MPEP §2106.05(f)). No further active steps are recited so as to add significantly more to the judicial exception.
Therefore, claims 63-66 are rejected under 35 USC §101 as being directed towards patent ineligible natural phenomena and abstract ideas, failing to integrate or add substantially more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
Claim Rejections - 35 USC § 112
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 63-66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of CXCR4 antagonists without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses 2 examples of CXCR4 antagonist (see page 5 at paragraph 0008). The genus of CXCR4 antagonists includes small molecules, peptides, and antibodies which are biologically distinct classes. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of CXCR4 antagonists as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, peptides, small molecules, and/or antibodies (including those yet to be discovered) might be included in the genus as antagonizing CXCR4 in a way that is therapeutic for severe Covid-19 (interpreted to mean Covid-19-induced ARDS as noted in the claim interpretation above) or ARDs.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed 2 species of CXCR4 antagonists for consideration.
Hamshaw et al (Biochem Pharmacol. 2023 Dec;218:115921. doi: 10.1016/j.bcp.2023.115921. Epub 2023 Nov 11) teach that, as of 2023, To date, the only US Food and Drug Administration approved CXCR4 antagonist is AMD3100 (Plerixafor, Mozobil ®) which is used for autologous stem cell transplantation in patients with multiple myeloma and non-Hodgkin’s lymphoma. While there are many CXCL12/CXCR4-based antagonists in pre-clinical trials including CXCR4 antibodies, peptide inhibitors, natural products, small molecule compounds and microRNAs, only a few have entered clinical trials, reviewed in Zhao et al. This is due to many CXCR4 antagonists having poor efficacy and/or toxicity (see for example, column 2 of page 1 bridging column 1 of page 2).
Thus, given the limited number of defined species of the genus described by the state of the art as of the effective filing date as well as the high level of unpredictability in the art, the disclosure of only 2 species of CXCR4 antagonists is not sufficiently representative of the entire genus claimed (encompassing antagonists not described or even invented).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CXCR4 antagonists that confer upon an antagonist the ability to function as claimed because the instant specification does not provide structural features that correlate with an ability to function as therapeutically as claimed.
Absent a clear description of the at least minimal structural features correlating with an ability to function as claimed which are shared by members of a genus commonly sharing this therapeutic function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CXCR4 antagonists would reliably possess an ability to function as claimed.
The specification does not disclose the structure required for the claimed CXCR4 antagonist genus and fails to disclose which structures are responsible for the therapeutic functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
Accordingly, claims 63-66 are rejected under 35 USC 112(a) because the CXCR4 antagonists of claims 65-66 fail to meet the written description requirement and claims 63-64 being directed to methods for treating ARDS or severe Covid-19 are broader in scope and therefore reflect the same lack of written description of the clearly encompassed genus of CXCR4 antagonists.
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 63-66 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.
Regarding claim 63, the preamble recites a method comprising administering treatment for acute respiratory distress syndrome (ARDS) or severe COVID-19 to a subject exhibiting a concentration of stromal cell- derived factor 1 (SDF1) protein in a blood, serum, or plasma sample from the subject at admission to ICU or early onset of ARDS that is equal to or higher than a reference concentration. This reference concentration is defined at paragraph 0047 of page 14 of the instant specification as “the term control sample, control level, reference concentration, or control subject, refer to a sample, level, or subject that is considered "normal" or "wild-type" relative to the specific condition or conditions under investigation. For example, a biomarker control level is the level of the biomarker identified in a subject or a cohort of subjects (e.g., pooled samples, or averaged values) that are not symptomatic for, and have no known precondition for developing a disease or condition in question ( e.g., ARDS and in particular severe ARDS).” With more specific definition at paragraph 0054 of page 17 of the instant specification providing that “In even further embodiments, if the
detected concentration and/or reference concentration is at least about 1 ng/ml, 2 ng/ml, 3 ng/ml,
4 ng/ml, 5 ng/ml, 6 ng/ml, 7 ng/ml, 8 ng/ml, 9 ng/ml, 10 ng/ml, 11 ng/ml, 12 ng/ml, 13 ng/ml, 14
ng/ml, 15 ng/ml, or higher, then the subject is treated for ARDS, in particular severe ARDS.” Both of these descriptions fail to adequately and clearly convey the reference concertation used in the method (which determines if the subject is administered the treatment of not). Artisans are left to discover the reference concentration which clearly serves as the cutoff point determining if the subject is administered treatment. The artisan cannot know and must discover the metes and bounds of the claim scope as drafted. Two artisan using different reference values would be practicing different methods, neither or both of which may be deemed to infringe the claim or not as presently drafted.
Claims 64-66, via dependency, incorporate and fail to remedy this ambiguity and are therefore included in this rejection.
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.
Claim(s) 63-65 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isles et al (Front. Immunol. 10:1784. doi: 10.3389/fimmu.2019.01784; as cited on the 04/24/2024 IDS as citation 44 under Non-Patent Literature) in view of Fan et al (The Lancet Respiratory Medicine, 2020; 8, 816-821), Nassoiy et al (Clin Exp Pharmacol Physiol. 2018 Jan;45(1):16-26. doi: 10.1111/1440-1681.12845. Epub 2017 Sep 20; as cited on the 04/24/2024 IDS as citation 46 under Non-Patent Literature), and Petty et al (J Immunol. 2007 Jun 15;178(12):8148-57. doi: 10.4049/jimmunol.178.12.8148; as cited on the 04/24/2024 IDS as citation 45 under Non-Patent Literature).
Regarding claims 63-64, Isles et al teach that the inappropriate retention of neutrophils at inflammatory sites is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS, and cystic fibrosis. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Isles et al investigates the role of the CXCL12/CXCR4 signaling axis in modulating neutrophil retention at inflammatory sites. Isles et al used an in vivo tissue injury model to study neutrophilic inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridization and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signaling axis pharmacologically. Isles et al identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signaling axis accelerated resolution of the neutrophil component of inflammation, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signaling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung (see for example, the abstract at page 1; note that CXCL12 is taught to by synonymous with SDF-1 at exemplary paragraph 2 of column 2 of page 2). Pharmacologic inhibition of CXCR4 was accomplished by administering AMD3100 (see for example, page 6 of Isles et al). Isles et al further teach that CXCL12/CXCR4 signaling is a key retention signal for neutrophil release into the blood circulation from hematopoietic tissues, the crucial role of which is highlighted in patients with infection.
Isles et al do not specifically or explicitly mention Covid-19.
However, Fan et al teach that the COVID-19 pandemic has seen a surge of patients with acute respiratory distress syndrome (ARDS) in intensive care units across the globe. Fan et al further teach that Although early reports suggested that COVID-19-associated ARDS has distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics of patients with ARDS, with or without COVID-19, are broadly similar (see for example, the abstract at page 816). Fan et al also support that Covid-19 is synonymous with SARS-CoV-2 (see for example, the search strategy and selection criteria box at the upper right-hand corner of page 819).
The Examiner believes Isles et al in view of Fan would motivate the artisan to administer AMD3100 to a human for treating ARDS, such as severe-Covid-19-induced/associated ARDS. However, augmenting the rationale to apply the teachings of Isles et al to a mammalian (including human) model, Nassoiy et al teach and confirm previous reports suggesting therapeutic potential of CXCR4 agonists (such as AMD 3100; see for example the abstract at page to attenuate lung injury in various animal models, establish a cause-effect relationships for the effects of pharmacological CXCR4 modulation on the development of ARDS after lung ischemia-reperfusion injury, and provide initial pre-clinical evidence that CXCR4 agonists could be used to attenuate progression of mild ARDS to moderate and severe ARDS. Nassoiy et al teach CXCR4 as a drug target to reduce the incidence and attenuate the severity of ARDS (see for example, page 7). Nassoiy et al further teach that, while there is no single animal model that is able to resemble all aspects of the human pathophysiology, lung-ischemia reperfusion injury is a well-accepted model that reflects key features of human ARDS (see for example, paragraph 2 of the Discussion at page 4).
Isles et al, Fan et al, and Nassoiy et al do not teach comparison of an SDF-1 level from a sample to a reference concentration so as to provide a cutoff point at which a CXCR4 antagonist would be needed to be administered (such as when Covid-19-associated ARDS is present/underway).
However, Petty et al examined SDF-1 expression by immunohistochemistry (IHC) both in human lung samples from patients with histologic evidence of acute lung injury (ALI) and in murine lungs 24 h after injury with nebulized LPS as a model of ALI. Limited staining is present in both normal (uninjured) human (Fig. 1A) and mouse (Fig. 1C) lungs, primarily in the alveolar epithelium and possibly alveolar macro phages. Following the development of injury, both human (Fig. 1B) and mouse (Fig. 1D) lungs show markedly increased SDF-1 staining. Staining appears to become diffuse during ALI, in volving both the alveolar epithelium (particularly what appear morphologically to be type II cells) and the interstitium. Murine tissue staining was performed using the same anti-SDF-1 antibody (Ab) as that used on human tissues (clone 79018, R&D Systems) and shows a more limited but similar SDF-1 staining pattern compared with the human ALI-affected lung. These findings indicate increased SDF-1 expression in both human and murine lungs during ALI. Serum levels of SDF-1 were found to rise in a similar fashion (Fig. 2B), noting that 0.8 ng/ml and beyond was disclosed to be a statistically significant protein increase, suggesting a cutoff/reference value of anything higher than 0.8ngl/ml of serum SDF-1 as a point at which treatment for ARDS should be given in response to the presence of ARDS (see for example, Fig. 2B and its caption at page 8151 and page 8152; see also exemplary column 2 of page 8154 teaching that SDF-1 appears to play a causal role in the recruitment of neutrophils to the lung in response to LPS injury).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to treat Covid-19-associated/induced ARDS, which is taught to be similar in pathology and for management/treatment, to classic (non- Covid-19-associated/induced) ARDS by administering a CXCR4 antagonist such as AMD3100 to address neutrophil accumulation in the lung, a driving mechanism of ARDS, by promoting reverse migration of the neutrophils (taught to be therapeutic for ARDS), where the need for ARDs treatment is measured by a measured serum level equal to or greater than 0.8ng/ml, which includes a value of 1 ng/ml or greater. The artisan would have been so motivated and would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 65, as discussed above, the combined references teach and motivate, making obvious, administration of a CXCR4 antagonist for treating Covid-19-associated/induced ARDs based upon a measured serum level equal to or greater than 0.08ng/ml (which meets the recited reference concentration, see the claim interpretation section of this Office Action above).
Claim(s) 66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isles et al, Fan et al, Nassoiy et al, and Petty et al, as applied to claims 63-65 above, in view of Song et al (Exp Mol Med 42, 465–476 (2010). https://doi.org/10.3858/emm.2010.42.6.048).
Regarding claim 66, as discussed above, the combined references teach and motivate, making obvious, administration of a CXCR4 antagonist for treating Covid-19-associated/induced ARDs based upon a measured serum level equal to or greater than 0.08ng/ml (which meets the recited reference concentration, see the claim interpretation section of this Office Action above).
The combined references do not explicitly teach administration of the CXCR4 antagonist for no more than 3 days.
However, Song et al teach that CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1). AMD3100 treatment in mice decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) (see for example, the abstract of Song et al at page 465).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the combination of Isles et al, Fan et al, Nassoiy et al, and Petty et al teach treatment of a subject having covid-19-associated/induced ARDS (as measured by an SDF-1 serum level at or over 0.8ng/ml (reading on the recited reference concentration)) by administering a CXCR4 antagonist, such as AMD3100. The artisan would have found it obvious to treat the subject for 3 days specifically because Song et al teach that 3 days is sufficient to decrease the SDF-1 mRNA expression and fibrocyte numbers in the lung (which aids in preventing pulmonary fibrosis). The artisan would understand that a shorter treatment duration decreases risks of side-effect, toxicities, and enhances medication compliance. In regards to the specific dosage and interval amounts recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges/regimens involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same method to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens (such as the length of treatment). Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious. Discovery that treatment is optimized when given for no longer than 3 days would have been a result effective variable to optimize for treating ARDS as taught in the prior art. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Vaart et al (Adv Hematol. 2012;2012:159807. doi: 10.1155/2012/159807) teach that the zebrafish (the primary model used by Isles et al) has proven itself as an excellent model to study vertebrate innate immunity. It presents us with possibilities for in vivo imaging of host-pathogen interactions which are unparalleled in mammalian model systems (see for example the abstract at page 1).
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights