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 . 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.
Information Disclosure Statement
The information disclosure statement filed 24 July, 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. No copy was found that definitively matched Nayak et al (NPL 6), and Haun et al (NPL9) had overlapping text and headers that hid significant amounts of the article. Thus, these references were not considered.
Election/Restrictions
Applicant's election with traverse of group I (method of treating sepsis and sepsis related conditions), specifically, C1q to treat pneumonia in the reply filed on 12 Jan, 2026 is acknowledged and the phone call with Frank Vandervegt on 10 Feb, 2026. The traversal is on the ground(s) that there is no search burden to search the claims in their entirety. This is not found persuasive because, as an application filed under 35 USC 371, search burden is not the basis of election/restriction.
The requirement is still deemed proper and is therefore made FINAL.
Applicants elected treating pneumonia with C1q. A search was conducted for this invention, and references were found that rendered this invention obvious. As a result, claims 1, 3-7, and 11 were examined and claims 2, 8-10, and 12-20 were withdrawn from consideration.
Claims Status
Claims 1-20 are pending.
Claims 2, 8-10, and 12-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12 Jan, 2026.
Drawings
The drawings are objected to because they use color, note the heatmap of fig 1E. Applicants are required to either delete the drawing or amend it so it does not need color for interpretation. If applicants are unable to delete or amend without losing information they believe to be important, they can petition for color drawings. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
first rejection, scope of enablement
Claims 1, 3-7, and 11 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 sepsis related disorders related to immune system dysfunction, does not reasonably provide enablement for all sepsis related disorders. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The MPEP states “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue.’ These factors include, but are not limited to: 1) the breadth of the claims; 2) the nature of the invention; 3) the state of the prior art; 4) the level of one of ordinary skill; 5) the level of predictability in the art; 6) the amount of direction provided by the inventor; 7) the existence of working examples; and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure” (MPEP 2164.01(a).
1 and 2) the breadth of the claims and the nature of the invention: Applicants are claiming treatment of sepsis and sepsis related disorders with C1q. There is no limitation requiring that the individual with the sepsis related condition also have sepsis.
3) the state of the prior art: Bohlson et al (Front. Immunol. (2014) 5(401), cited by applicants) teaches that C1q has many functions in the immune system, both directly binding to pathogens and macrophages (abstract). This reference shows that applicant’s invention works by manipulating the immune system.
Hotchkiss et al (Nat. Rev. Dis. Primers (2016) 2 article 16045) teaches that hypotension is an effect of septic shock (abstract). In other words, hypotension is a sepsis related disorder.
Friedlander (Medicine (1927) 4(2) p143-339) teaches that hypotension can be caused by anesthesia (p180, 3d paragraph), possibly to fatal levels (p180, 4th paragraph), blood loss due to injury (p183, 1st paragraph), diabetes complications (p205, 3d paragraph), Addison’s disease (p206, 6th paragraph), starvation (p208, 2nd paragraph), and other non-infection or immune system based causes.
4) the level of one of ordinary skill: The level of skill in the art is high.
5) the level of predictability in the art: Hotchkiss et al states that in-hospital mortality rates for sepsis are 30-50% (abstract), indicating that there is a low level of predictability in the art.
6 and 7) the amount of direction provided by the inventor and the existence of working examples: Applicants discuss a subpopulation of neutrophils in sepsis patients associated with higher mortality (paragraph 113). mRNA expression suggests low production of C1q in those cells (paragraph 115). Additional experiments merely confirm the activity of this protein in the immune system.
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure: Both applicants and the prior art show that C1q is an immune system modulator. Yet there are a number of causes of hypotension that are not immune related, or are only indirectly related to the immune system. This means it will take undue experimentation to use the invention as claimed for its entire scope.
second rejection, written description
Claims 1, 3-7, and 11 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is which C1q proteins and variants are effective in the invention.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: C1q protein is defined as the complement protein C1q, variants, homologous sequences, fragments, and other amino acid sequences having sequence identity to C1q protein (paragraph 26). Under the broadest reasonable interpretation, this is any amino acid sequence with at least 2 amino acids matching those in any C1q homolog. There is a mention of conservative substitutions (paragraph 28), but no other teaching of which parts of the sequence are important for the activity required in the invention.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming a treatment of sepsis and sepsis related disorders, comprising administering C1q, which is defined as any polypeptide that has identity to native C1q, or fragments. This requires that the protein have a beneficial effect in these disorders, a functional requirement. However, applicants have not described which of these possible C1q variants will provide a beneficial effect. A person of skill in the art, armed with applicant’s disclosure, would not know what sequence/aromaticity/hydrophobicity is required at which locations in the protein to have this function. In essence, a critical portion of applicant’s invention is defined by function. That is not sufficient to meet the written description requirement.
Applicants discuss a subpopulation of neutrophils in sepsis patients associated with higher mortality (paragraph 113). mRNA expression suggests low production of C1q in those cells (paragraph 115). Additional experiments merely confirm the activity of this protein in the immune system. Note that there is no mention of the function of C1q in the claimed disorders.
It is known in the art that C1q has multiple effects and binding partners. Bohlson et al states that the protein binds to multiple pathogen moieties, and to antibodies, part of the complement pathway (1st page, 1st column, 1st paragraph). It binds to macrophages by a number of different receptors at different parts of the protein (2nd page, 2nd column, 1st paragraph, continues to 3d page, 1st column, 1st paragraph). Note that applicants have not provided any information as to what the protein must bind to for a beneficial effect.
At the present state of the art, it is not possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants have data suggestive that a neutrophil associated with poor prognosis in sepsis does not produce large amounts of C1q. There is no description of what parts of the protein are important for activity; and it is known that different activities use different parts of the protein. Given that random mutations are likely to abrogate activity, it is not possible to modify the native sequence with assurance that appropriate activity will be maintained. Thus, applicant’s claims lack written description.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-7, and 11 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, and claims dependent on it, allow for variants of C1q, defined as a polypeptide that differs from C1q by one or more amino acids, but substantially maintains the biological function of the protein. There are two issues with this definition. The first is that C1q has multiple biological functions, as noted in the written description rejection above. If a polypeptide has some functions, but not others, it is not clear if it is a variant as defined by applicants. The second is the term “substantially.” The cutoff between substantially maintaining a function and not substantially maintaining a function is not defined by applicants.
Likewise, C1q is defined as allowing for amino acid sequences with sequence identity. However, the amount of sequence identity needed is not defined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
first rejection
Claim(s) 1, 3, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Meijvis et al (J. Int. Med. (2012) 272 p25-35) in view of Bohlson et al (Front. Immunol. (2014) 5(401), cited by applicants).
Meijvis et al discuss anti-inflammatory drugs for treating pneumonia (title). There can be an extended inflammatory response despite treatment with appropriate antibiotics, suggesting adjuvant anti-inflammatory therapy (abstract). Patients present with inflammation upon admission to the hospital (p27, 1st column, 2nd paragraph). Lung homoeostasis is a delicate balance of pro and anti-inflammatory responses; excessive inflammation can be life threatening (p28, 1st column, 1st paragraph). While this will not be beneficial for all pneumonia patients (p33, 1st column, 2nd paragraph), the authors state that anti-inflammatory medication can be useful for a subgroup of patients with an excessive immune response (p33, 1st column, 3d paragraph).
The difference between this reference and the examined claims is that this reference does not use C1q as an anti-inflammatory agent.
Bohlson et al discuss the complement system with respect to macrophages (title). C1q stimulates enhanced phagocytosis and diminution of pro-inflammatory cytokine production (5th page, 1st column, 1st paragraph). The complement protein also induced production of anti-inflammatory cytokine production, such as IL10, and dampens transcription activity of pro-inflammatory NF-kB heterodimers (5th page, 1st column, 2nd paragraph). This reference shows that C1q is an anti-inflammatory agent, and also increases phagocytosis by macrophages (useful for a bacterial infection).
Therefore, it would be obvious to use the C1q as part of the anti-inflammatory therapy of Meijvis et al, as Meijvis et al teaches anti-inflammatory therapy is useful for some pneumonia patients, and Bohlson et al teaches that C1q is also anti-inflammatory. As this protein works by multiple mechanisms, and also promotes engulfment by macrophages (useful for a bacterial infection), an artisan in this field would attempt this therapy with a reasonable expectation of success.
Meijvis et al et al and Bohlson et al together render obvious treatment of some pneumonia patients with C1q, rendering obvious claims 1 and 11.
Meijvis et al teaches antibiotic therapy for pneumonia, rendering obvious claim 3.
second rejection
Claim(s) 1, 3, 4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Meijvis et al (J. Int. Med. (2012) 272 p25-35) in view of Bohlson et al (Front. Immunol. (2014) 5(401), cited by applicants) and Labris et al (Br. J. Clin. Pharmacol. (2003) 56 p588-599).
The teachings of Meijvis et al and Bohlson et al were given above, and will not be repeated here. Note that these references render obvious claims 1, 3, and 11.
The difference between these references and the remaining claim is that these references do not disclose an administration route.
Labris et al discuss pulmonary drug delivery (title), i.e. inhalation. For treatment of respiratory disorders, such as the pneumonia of Meijvis et al, this provides several advantages over systemic administration, including high drug concentrations at disease site, minimizing systemic side effects, and smaller doses than systemic administration (table 1, p589, top of page). This reference discusses advantages of inhalation dosing for pulmonary diseases vs. systemic dosing.
Therefore, it would be obvious to use the inhalation dosing of Labris et al, to increase dosing in the lungs, minimizing systemic side effects, and to minimize the amount of drug used, as described by Labris et al. As there is extensive research and experience with inhalation dosing, an artisan in this field would attempt this administration route with a reasonable expectation of success.
third rejection
Claim(s) 1, 3, 5-7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Meijvis et al (J. Int. Med. (2012) 272 p25-35) in view of Bohlson et al (Front. Immunol. (2014) 5(401), cited by applicants) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
The teachings of Meijvis et al and Bohlson et al were given above, and will not be repeated here. Note that these references render obvious claims 1, 3, and 11.
The difference between these references and the remaining claims is that these references do not discuss a dose and dose schedule.
Le Tourneau et al discusses phase I clinical trials (title). The main goal of these studies is to determine the recommended dose and dose schedule for new drugs and drug combinations (abstract). The goal is to avoid subtherapeutic doses while maintaining safety and rapid accrual (p708, 1st column, 2nd paragraph). For less toxic drugs, the occurrence of drug related biological effects can be used as an endpoint (p708, 2nd column, 1st paragraph). A number of different dose escalation methods are discussed for achieving these goals (fig 2, p711, top of page). This reference discusses how to optimize a dose and dose schedule of a drug.
Therefore, it would be obvious to optimize the dose and dose schedule of the C1q of Bohlson et al, to minimize toxicity and subtherapeutic dosing while achieving rapid accrual of the drug. As every drug used has to have the dose and dose schedule optimized, this is a common exercise in the art, leading to a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658