DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is the 371 national stage entry of PCT/EP2023/052629, filed 2/3/2023, which claims priority to EP22155028.8, filed 2/3/2022. The priority date of 2/3/2022 is acknowledged.
Claim Status
Claims 16-32 are new and pending. Claims 1-15 are cancelled.
Information Disclosure Statement
The information disclosure statements filed on 10/22/2024 and 10/22/2025 are under consideration.
Examiner’s Note
A rejection under 35 U.S.C. 112(a) for written description was considered for claims 16-32 but not rendered. One skilled in the art would know how to incorporate the modifications of claim 16 to generate a variant of SEQ ID NO: 1 based on the teachings of Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited in the IDS filed 10/22/204.), which describes the importance of amino acids 74–78 and two typical heparin-binding motifs (BBXB and BBBXXB), present in SEQ ID NO: 1, removal of which causes SEQ ID NO: 1 to lose its ability to inhibit neutrophil migration (see Pg 7, “CXCL9 peptides inhibit CXCL8- and MSU crystal-induced neutrophil recruitment in vivo”).
Claim Rejections - 35 USC § 112
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 16-17 and 20-32 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 16 recites administering a peptide of up to 40 amino acids and comprises amino acids 74-103 of CXCL9 (SEQ ID NO: 1). Claim 17 similarly recites that the peptide is up to 35 amino acids. The scope of each of these claims is indefinite because the claim indicates that the polypeptide is open to additional elements not expressly recited based on the phrase “comprising” but also recites length limitations of up to 35 or up to 40 amino acids. Thus, it is unclear whether the full-length polypeptides of the claim are limited to polypeptides consisting of 35-40 amino acids or are open to polypeptides comprising amino acids 74-103 of CXCL9.
For purposes of examination, the peptide will be interpreted as a peptide comprising amino acids 74-103 of CXCL9 (SEQ ID NO: 1).
Further, by virtue of their dependency on claim 16, claims 20-32 are also hereby rejected for this same reasoning.
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 16-32 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 inflammation of lung tissue in a patient with a lung infection, does not reasonably provide enablement for preventing inflammation of lung tissue in a patient with a lung infection. 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 Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The claims are drawn to a method of treating or preventing inflammation of lung tissue in a patient suffering from a lung infection, comprising administering to the patient a peptide comprising SEQ ID NO: 1 or a variant thereof, wherein the variant comprises a modification selected from the group recited in claim 16 or a combination of modifications thereof. Treating and preventing as claimed reads on administering a polypeptide as described above to any individual with or without inflammation of lung tissue caused by a lung infection, as prevention does not require a subject in need to have a lung infection. However, the prior art does not teach that lung infections, and the inflammation they cause, can be prevented.
2) State of the prior art and 4) predictability or unpredictability of the art: The prior art at the time of filing teaches recruitment of neutrophils to the site of infection is an essential part of treating lung infections, involving both innate and adaptive immunity (Craig et al., Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009 Feb;77(2):568-575., as cited on IDS filed 10/22/2024). This is exemplified by studies demonstrating increases in the production and presence of immature neutrophils in the lungs in response to infection and selective depletion of neutrophils limits the clearance of bacteria for the lungs while repletion restores host defense (Pg 568, left column, first paragraph, and right column, “Neutrophils,” first paragraph). Figure 1 of Craig further demonstrates the process by which bacterial infections attract neutrophils to the lung, which involves interactions with cells in the alveoli and induction of cytokines and neutrophil chemoattractants.
Based on these teachings, one skilled in the art would reasonably predict that administration of SEQ ID NO: 1 or a variant thereof would not be able to prevent lung inflammation caused by an infection because neutrophils would not migrate to the site of an infection without the molecular cues that signal the presence of an infection in the first place. Thus, one skilled in the art would reasonably predict that the instant claims would not successfully prevent inflammation of lung tissue in a patient suffering from a lung infection.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable the prevention of inflammation of lung tissue caused by an infection as claimed.
7) The presence or absence of working examples: None of the examples set forth in the instant application demonstrate prevention, where administration of SEQ ID NO: 1 or a variant thereof prior to an infection ultimately reduces lung tissue inflammation.
8) The quantity of experimentation necessary: Because there are no examples in either
the prior art or the instant specification, reasonable guidance with respect to administering SEQ ID NO: 1 or a variant thereof to prevent inflammation of the lung caused by an infection was lacking. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively prevent said inflammation.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide sufficient information to practice the claimed invention.
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(s) 16-27 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over of Craig et al. (Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009 Feb;77(2):568-575., as cited on IDS filed 10/22/2024) in view of Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited on IDS filed 10/22/204.).
Craig teaches one of the most important components of the initial innate immune response in the lung against bacterial infection is the vigorous recruitment of neutrophils. However, several life-threatening bacterial lung diseases are caused by excessive neutrophil-mediated inflammation (Abstract). Figure 1 of Craig further demonstrates the process by which bacterial infections attract neutrophils to the lung, which involves interactions with cells in the alveoli and induction of cytokines and neutrophil chemoattractants that encourage the migration of neutrophils into the lungs.
In other words, Craig teaches that neutrophils are attracted to a site of lung infection by the cytokines and chemoattractants released in response to infection.
Craig does not teach administering SEQ ID NO: 1 as a means to treat said inflammation of lung tissue in a patient suffering from a lung infection.
Vanheule teaches several acute and chronic inflammatory diseases are characterized by enhanced expression of chemokines and accumulation of activated leukocytes in tissues. Some chemokines are secreted by tissue cells and resident leukocytes upon infection or tissue damage, thereby creating a gradient along which leukocytes can migrate from the blood vessel to the site of inflammation. To create such a leukocyte migration inducing gradient, it is necessary that chemokines are presented on the endothelium at the site of inflammation through binding to glycosaminoglycans (GAGs), thereby preventing chemokine diffusion and degradation and retaining high local chemokine concentrations. Subsequently, GAG-bound chemokines interact with their G protein-coupled receptors (GPCRs), expressed by specific circulating leukocyte subtypes. This results in adhesion to and extravasation of leukocytes through the endothelium. Once leukocytes enter the tissue, they can migrate to the site of inflammation through the gradient of local GAG-bound chemokines. The binding of chemokines to GAGs has been proven to be indispensable for chemokine activity in vivo.
Because of their essential role for the migration of leukocytes, chemokines and their GPCRs can serve as potential targets for the development of new anti-inflammatory drugs. Recently, intact modified chemokines were developed that interfere with the binding of chemokines to GAGs. These modified chemokines have, in comparison with their natural human chemokine counterpart, an enhanced affinity for GAGs but a decreased affinity for their GPCRs. In this way, the modified chemokines or decoy chemokines can compete with functional chemokines for GAG binding. Thereby, they reduce chemokine immobilization and presentation and enhance the inhibition of chemokine-induced leukocyte migration.
More recently, COOH-terminal peptides of the chemokine CXCL9 or monokine induced by interferon-γ (MIG) were described as potent GAG-binding peptides. The CXCL9(74-103) peptide, which is identical to the instant SEQ ID NO: 1, inhibits in vivo chemotactic activity of CXCL8 by competing with CXCL8 for the binding to GAGs. Also, in a murine model of monosodium urate (MSU) crystal-induced gout, the peptide was able to inhibit neutrophil extravasation (Pg 2, “Introduction”).
Effectively, Vanheule teaches a method of treating acute inflammation by administration of SEQ ID NO: 1, wherein SEQ ID NO: 1 is capable of competitively binding to GAGs to block their interactions with chemokines that further attract neutrophils to a site of inflammation.
In summary, Craig teaches that neutrophils are attracted to a site of lung infection by the cytokines and chemoattractants released in response to infection, which can result in excessive neutrophil-mediated inflammation in certain cases. Vanheule teaches a method of treating acute neutrophil-mediated inflammation by administration of SEQ ID NO: 1.
Thus, regarding claim 16, it would be prima facie obvious to apply the method of Vanheule to treat lung inflammation induced by an infection. One of ordinary skill in the art would be motivated to do so because Craig teaches that bacterial lung infections similarly elicit neutrophil migration and inflammation. Further, one would have a reasonable expectation of success as one would recognize that the mechanism by which SEQ ID NO: 1 treats inflammation could be applied to treat any inflammation caused by neutrophil-induced migration and accumulation.
Regarding claims 17-19, as stated above, Vanheule teaches a peptide consisting of SEQ ID NO: 1.
Regarding claim 20, as stated above, Craig teaches bacterial lung infections (Title, Pg 568-569, Figure 1).
Regarding claims 21-24, Craig teaches the bacterial species Klebisella pneumoniae (Pg 568, right column, “Neutrophils”).
Regarding claims 25-26, Craig teaches the bacterial species Staphylococcus aureus and Stroptococcus pneumoniae (Pg 568, left column, first paragraph).
Regarding claim 27, Craig teaches several species resistant bacteria, including S. pneumoniae, H. influenzae, and S. aureus (Pg 568, left column, “Clinical importance”).
Regarding claim 29, Vanheule teaches intraperitoneal administration (Pg 7, left column, “CXCL9 peptides inhibit CXCL8- and MSU crystal-induced neutrophil recruitment in vivo, first paragraph)).
Claim(s) 16-29 are rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009 Feb;77(2):568-575., as cited on IDS filed 10/22/2024), and Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited on IDS filed 10/22/204.), as applied to claims 16-27 and 29 above, and further in view of Johansson et al. (Neutrophils in respiratory viral infections. Mucosal Immunol. 2021 Jul;14(4):815-827.).
The teachings of Craig and Vanheule have been set forth above. Craig and Vanheule do not teach a method of treatment wherein the lung infection is a viral infection.
Johansson teaches viral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established (Abstract).
During inflammation, neutrophil transmigration to the affected tissue occurs in a step-wise process known as the leukocyte adhesion cascade. Many neutrophil chemoattractants are produced in the lungs and airways during viral infections, for example, CXCL1, CXCL2 and IL-17, resulting in neutrophil infiltration into the lungs of mice and ferrets. During RSV infection in mice this infiltration to the lungs is transient as neutrophils peak at 18 h postinfection (p.i.) and are almost absent by 36 h p.i. This is different during severe mouse IAV infection, in which neutrophils chemoattractants such as CXCL1 and neutrophils remain in the lungs for a longer time and are still detectable at day 12 p.i., especially when a highly pathogenic IAV strain is used. This would suggest that a sustained neutrophil recruitment and/or presence in the lungs is associated with more severe disease (Figure 1).
Thus, Johansson teaches neutrophils are recruited to the lung in response to an RSV infection (Pg 816, left column, “Neutrophil recruitment,” second paragraph).
Based on these teachings, regarding claim 28, it would be prima facie obvious to apply the method of Craig and Vanheule to treat a viral infection such as RSV. One skilled in the art would be motivated to do and have a reasonable expectation of success as Johansson teaches viral infections, like bacterial and fungal infections, similarly cause recruitment of neutrophils to the lungs.
Claim(s) 16-27 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009 Feb;77(2):568-575., as cited on IDS filed 10/22/2024) and Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited on IDS filed 10/22/204.), as applied to claims 16-27 and 29 above, and further in view of Lorenzo et al. (Lung inflammatory pattern and antibiotic treatment in pneumonia. Respir Res. 2015 Feb 7;16(1):15.; abstract only).
The teachings of Craig and Vanheule have been set forth above. Craig and Vanheule do not teach a method of treatment wherein the peptide is co-administered with an antibiotic compound.
Lorenzo teaches that in community-acquired pneumonia host inflammatory response against the causative microorganism is necessary for infection resolution. However, an excessive response can have deleterious effects. In addition to antimicrobial effects, macrolide antibiotics are known to possess immunomodulatory properties (Background). Lorenzo teaches treating patients with macrolide antibiotics improves the inflammatory response as compared to patients treated with non-macrolide regimens. Further, patients treated with macrolide regimens required fewer days to reach clinical stability and shorter hospitalization periods (Results).
Thus, Craig and Vanheule teach a method of treating lung tissue inflammation caused by lung infection in a patient in need thereof. Lorenzo teaches administering macrolide antibiotics to patients with community-acquired pneumonia to treat both inflammation caused by the infection as well as the infection itself. Therefore, regarding claim 30, it would be prima facie obvious to co-administer the macrolide antibiotic taught by Lorenzo as part of the method of Craig and Vanheule. One skilled in the art would be motivated to do and have a reasonable expectation of success as Lorenzo teaches administration of macrolide antibiotics treats both the inflammation and infection.
Claim(s) 16-27, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (Neutrophil recruitment to the lungs during bacterial pneumonia. Infection and Immunity. 2009 Feb;77(2):568-575., as cited on IDS filed 10/22/2024) and Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited on IDS filed 10/22/204.), as applied to claims 16-27 and 29 above, and further in view of Chen et al. (Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol 15, 938–946 (2014).).
The teachings of Craig and Vanheule have been set forth above. Craig and Vanheule do not teach a method of treatment wherein the lung infection is a parasitic infection.
Chen examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis (Abstract).
Chen teaches neutrophils infiltrate the lung at day 2 after primary N. brasiliensis inoculation (Pg 942, “Protection in secondary infections requires neutrophils”).
Based on these teachings, regarding claim 31, it would be prima facie obvious to apply the method of Craig and Vanheule to treat an infection caused by a parasite such as N. brasiliensis. One skilled in the art would be motivated to do and have a reasonable expectation of success as Chen teaches parasitic infections, like bacterial and fungal infections, similarly cause recruitment of neutrophils to the lungs.
Allowable Subject Matter
A peptide comprising SEQ ID NO: 2 is free of the art. The closest art is SEQ ID NO: 1, as described by Vanheule et al. ((2017) CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions. Front. Immunol. 8:530.; cited in the IDS filed 10/22/204.). The differences between SEQ ID NO: 1 and 2 are 1) the N-terminus of SEQ ID NO: 2 is acetylated, 2) all Lys residues of SEQ ID NO: 1 have been substituted to Orn residues, 3) the Val-Leu residues at positions 15 and 16 of SEQ ID NO: 1 are substituted to Gln-Gln, and 4) the Ser residue at position 24 of SEQ ID NO: 1 is substituted to Orn.
Vanheule teaches that the motifs BBXB and BBBXXB, in which B represents a basic and X represents any non-basic amino acid, are important for GAG binding. These motifs are present in SEQ ID NO: 1 at residues at positions 75-78 and 85-90; there is also a “reversed” GAG-binding domain (BXBB instead of BBXB) made up by the residues occupying positions 98-101.
Although N-terminal acetylation and modification of Lys residues to Orn to improve peptide stability is known in the art, it is not obvious to make the Val-Leu to Gln-Gln and Ser to Orn substitutions. It is not obvious to make the Val-Leu to Gln-Gln substitution as this substitution takes place in the middle of the BBBXXB motif at positions 85-90 and, although XX can be occupied by any non-basic residue, there is no motivation to select Gln as the substituted amino acid. Further, there is no teaching, suggestion, or motivation to substitute the Ser residue at position 24 to an Orn. Therefore, a peptide comprising SEQ ID NO: 2 is novel and non-obvious.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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