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 .
DETAILED ACTION
The amendment after non-final office action filed November 11, 2025 is acknowledged. Claims 1-15, 17-18, 20-21, 36 were cancelled, claim 19 was amended and claims 16, 19, 22-35, 37-40 are pending.
Election/Restrictions
The restriction requirement was deemed proper and made FINAL in a previous office action. Applicants previously elected SEQ ID NO:3 from List I, Infectious disease from List II and Imipenem as the additional agent in the response filed March 5, 2024. Claims 25-35, 37-40 remain withdrawn from consideration as being drawn to a non-elected invention/species.
Claims 16, 19, 22-24 are examined on the merits of this office action.
Declaration under 37 C.F.R. 1.132
The Declaration under 37 CFR 1.132 filed November 11, 2025 (referred to as “Soto 2” is insufficient to overcome the rejection of claims based upon Claims 16, 19, 22-24 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as set forth in the last Office action. Applicants argue “the three 11-mer peptides derived from the amino acid sequence of the CD6 protein of the claims of present application (i.e., SEQ ID NOs: 1-3) correspond to the peptides CD6.PD1 or SEP] (GTVEVRLEASW), CD6.PD2 or SEP2 (GRVEMLEHGEW) and CD6.PD3 or SEP3 (GQVEVHFRGVW), respectively.. The examples of the present patent application show that the peptides of SEQ ID NOs: 1-3 interact with bacterial PAMPs from Gram+ and Gram- bacteria and possess antibacterial activity. I hereby provide experimental evidence that the peptides also interfere with fungal endotoxins or fungal cell components to prevent fungal growth in different fungal species. We showed evidence of growth inhibition experiments of the fungus Cryptococcus neoformans in the presence of the peptide of SEQ ID NO: 3 (SEP3: GQVEVHFRGVW) in the previous Declaration filed on April 14, 2025. Our group has performed additional experiments (Figure 1) showing fungal damage of the mold Aspergillus fumigatus (ATTC 46645) in the presence of the peptide of SEQ ID NO: 3 (SEP3: GQVEVHFRGVW) at 10 and 50 ug/mL. The SEQ ID NO: 3 (SEP3) peptide effect on fungal damage was assessed by culturing Aspergillus fumigatus (2.5 x 10° CFU/well) in RPMI medium in the presence of two different concentrations of peptide (10 or 50 g/mL) in flat- bottom 96-well plates. RPMI medium in the presence of control scrambled peptide (SEP3- scrambled, of unrelated 11mer amino-acid sequence) was used as the negative control. Fungal cells without peptides (0 pg/mL) were used as the positive control. Fungal damage was determined by measuring in triplicate using an XTT Cell Proliferation Assay Kit (CA031, Canxav).
This new data for the mold Aspergillus fumigatus extends the fungal binding capacity of SEQ ID NO: 3 (SEP3:GQVEVHFRGVW), previously showed for the fungus C. neoformans, beyond yeasts, to include molds and Dimorphic fungi which switch between the mold and yeast forms. The results of the dose-related inhibitory capacity of SEQ ID NO: 3 (SEP3) at 0, 10 and 50 ug/mL concentrations are shown in Figure 1 below. The peptide shows a dose dependent fungal damage.
In summary, the above dose-related inhibitory capacity of SEQ ID NO: 3 (SEP3) indicates direct binding of the peptide to Aspergillus fumigatus PAMPs or cell wall components. These results, together with those of the previous experiments with Cryptococcus neoformans, are suggestive of a broad capacity of the peptide of SEQ ID NO: 3 to neutralize fungal toxins and to prevent and treat fungal infections caused by different species of fungi. All other peptides with evolutionary conserved sequences to SEQ ID NO: 3 (7.e., SEQ ID NOs: 1-3) would also be capable of fungal cell wall component interactions, and effective in the treatment and/or prophylaxis of fungal infections.”
Applicant’s arguments presented in the “Soto 2” declaration have been considered but are not persuasive. Although the declarations (including the previous “Soto” declaration) provides inhibition data for Cryptococcus neoformans and Aspergillus fumigatus, these two organisms are not representative of the full fungal genus encompassed by the claims, which include molds, yeasts, and dimorphic fungi responsible for a wide variety of distinct infections. As stated previously, Fungi are diverse and unpredictable group that differ substantially in cell was composition, morphology, pathogenic mechanisms, immune recognition, and expression of distinct PAMPs, and they cause sepsis or SIRS via different pathways. Accordingly, activity against C. neoformans and A. Fumigatus cannot reasonably be extrapolated to the broad range of pathogenic fungi such as Candida albicans, dimorphic fungi,mucromycoses, dermatophytes and other relevant species. The record continues to lack any evidence showing that SEQ ID NO:3, or any peptide of the claims, prevents fungal infection, prevents sepsis or SIRS, or prevents any bacteria or fungal infection as required for the prophylactic portion of the claims. Likewise, no evidence is provided demonstrating neutralization of fungal toxins or PAMPs beyond the limited species tested. With respect to Applicants reliance on Vera (reference cited in previous Arguments), the reference teaches that soluble CD6 protein (not the peptide fragments of the instant claims) binds to PAMPs from Schizosaccharomyces pombe, and Vera also reports that soluble CD6 failed to bind other fungal species, including C. albicans, thereby underscoring the unpredictability of fungal recognition and therapeutic response. Binding of a protein to PAMPs in a single fungal species does not establish that the claimed peptide fragments are capable of binding PAMPs from fungal species broadly or are capable of treating or preventing fungal infections as claimed. Taken together, testing only two fungal species (in light of the unpredictability of the prior art) is insufficient to eliminate the need for extensive additional experimentation across unrelated fungi to determine the efficacy required to practice the full scope of the invention which is inclusive to prevention. Therefore, neither declarations (Soto or “Soto 2”) demonstrate enablement commensurate with the claims and Applicants arguments that activity against C. neoformans and Aspergillus fumigatus, is sufficient to support treatment or prophylaxis of all fungal infections including fungal sepsis or SIRS are not persuasive.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 112
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, 19, 22-24 remain 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 treatment of specific bacterial infections/specific fungal infections does not reasonably provide enablement for treating or preventing ANY bacterial or fungal infection or inflammatory disease (SIRS or Sepsis) caused by the bacteria or fungi or the presence of a product derived from either microbe . 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.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of the claims
Claim 16 claims " A method for the treatment or prophylaxis of a disease or condition in a subject, wherein the disease or condition is bacterial infection, a fungal infection or combination thereof, bacterial septicemia, fungal septicemia or a combination thereof, or an inflammatory disease which is SIRS or sepsis caused by the presence of a product derived from bacterium or fungus, wherein said method comprises administering a therapeutically effective amount of one or more isolated amino acid sequences consisting of a sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 1, SEQ ID NO: 2, and derivatives thereof, wherein said derivatives are a peptide consisting of SEQ ID NO: 3, SEQ ID NO: 1, or SEQ ID NO: 2 with (i) one modification of a C- terminal end selected from C-amidation and C-esterification and/or one modification of an N- terminal end selected from N-acylation and N-alkylation, (ii) replacement of one or more L- amino acids with corresponding D-amino acids, (iii) conjugation with polyethylene glycol or albumin, or (iv) combinations of any of (i), (ii), or (iii) . The claims are broad with respect to the patient population/diseases or conditions to be treated or prevented (any fungal or bacterial infection, sepsis/SIRS caused by bacteria or fungal infection or products derived from bacteria or fungus.
Treatment of infectious disease and sepsis is an unpredictable art particularly involving diverse microorganisms and complex immune responses.
The State of the Prior Art
The Examiner is not aware of prior art disclosing the use of the claimed composition or any one composition for treatment/prevention of ANY bacteria or fungal infection and inflammatory conditions caused by said infections. However, art does exist with regards to treating specific bacteria with CD6 derived peptides.
Martinez-Florensa (cited in Applicant’s IDS and by inventors) teaches that Sepsis is an unmet clinical need constituting one of the most important causes of death worldwide, a fact aggravated by the appearance of multidrug resistant strains due to indiscriminate use of antibiotics. Host innate immune receptors involved in pathogen associated molecular patterns (PAMPs) recognition represent a source of broad-spectrum therapies alternative or adjunctive to antibiotics. Among the few members of the ancient and highly conserved scavenger receptor cysteine-rich superfamily (SRCR-SF) sharing bacterial-binding properties there is CD6, a lymphocyte-specific surface receptor. Here, we analyze the bacterial-binding properties of three conserved short peptides (11-mer) mapping at extracellular SRCR domains of human CD6 (CD6.PD1, GTVEVRLEASW; CD6.PD2 GRVEMLEHGEW; and CD6.PD3, GQVEVHFRGVW). All peptides show high binding affinity for PAMPs from Gram-negative (lipopolysaccharide; Kd from 3.5 to 3,000 nM) and Gram-positive (lipoteichoic acid; Kd from 36 to 680 nM) bacteria. The CD6.PD3 peptide possesses broad bacterial-agglutination properties and improved survival of mice undergoing polymicrobial sepsis in a dose- and time-dependent manner. Accordingly, CD6.PD3 triggers a decrease in serum levels of both pro-inflammatory cytokines and bacterial load. Interestingly, CD6.PD3 shows additive survival effects on septic mice when combined with Imipenem/Cilastatin. These results illustrate the therapeutic potential of peptides retaining the bacterial-binding properties of native CD6.” Thus, there is evidence that CD6 peptides have antibacterial activity. However, this is not enough to show that the peptides are capable of treating/preventing any bacterial/fungal disease or treating/preventing any inflammatory disorder caused by the bacteria/fungi or derived from the bacteria/fungi
The art does not establish that peptides with bacterial PAMP activity inherently function across ALL fungal species to treat/prevent infections or SIRS/sepsis caused by the presence of a product derived from bacteria or fungus.
The Predictability or Unpredictability of the Art
The treatment and prevention of bacterial and fungal infections, and sepsis/SIRS caused by pathogen derived products (bacterial and fungal), is highly unpredictable, as different pathogens and their toxins elicit diverse and non predictable biological responses; thus, therapeutic effectiveness of the claimed peptide derivatives cannot be reliably predicted without extensive testing.
The Relative Skill of Those in the Art
While those skilled in immunology or microbiology are highly trained, success in sepsis prevention or fungal therapy remains unpredictable and complex.
Amount of Guidance/ The Presence or Absence of Working Examples
In the instant case, Applicants reduce to practice the following: Applicants show that CD6 derived peptides (SEQ ID NO:1-3) have antibacterial activity and are effective treating mice with CLP-induced septic shock (see paragraph 0252, PGPUB, Example 1). In example 2, Applicants show that CD6 derived peptides bind bacterial Toxins (see paragraph 0261).
Figure 2 shows the agglutination properties of SEQ ID Nos:1-3 (PD1-PD3) and Figure 3 shows binding to PAMPs. The Examiner would like to point out that there is some variability in the data provided with regards to the peptides of the instant claims and treating sepsis. For example, PD1 peptide (SEQ IDNO:1) did not appear to be therapeutically effective in treating sepsis (see Figure 7). Thus, there is some unpredictability with regards to the peptides encompassed by the claims. Furthermore, in the declaration filed 4/18/2025, data was provided regarding instant SEQ ID NO:3 and the effect on C. neoformans. Figure 1 (page 3 of the Declaration) shows that there appears to be inhibition of C. neoformans at a concentration of 50 ug/mL Furthermore, in the declaration filed November 11, 2025, Figure 1 shows “fungal damage” of A. Fumigatus with instant SEQ ID NO:3. However, prevention is not shown. The instant claims cover all fungal infections, but no evidence is provided showing efficacy of the peptides against other clinically relevant fungi such as Candida albicans, histoplasma capsulatum or other fungi or prevention of any Fungi. Fungi vary widely in pathogenic mechanisms, cell wall structure and host immune responses. Cryptococcus and A. Fumigatus data is not representative of the entire fungal kingdom.
The specification does not show prevention of any infection. Treatment of existing specific bacterial infections and two strain of fungi, does not provide enablement for treatment or prevention of any bacterial or fungal infection or any sepsis or SIRS cause by said microbe or a product derived from said microbe.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed peptides would be effective at treating/preventing any bacterial or fungal infection or any sepsis or SIRS cause by said microbes or a product derived from said microbes. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation. Extensive screening would be needed across many diverse fungal species and across models of sepsis and SIRS.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Response to Applicant’s Arguments
Applicant respectfully disagrees and requests reconsideration. Briefly, with respect to enablement, nothing more than objective enablement is required. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). In particular, as stated by the Federal Circuit: [A] specification disclosure which contains a teaching of the manner and process of making and using the invention in terms which correspond in scope to those used in describing and defining the subject matter sought to be patented must be taken as in compliance with the enabling requirement of the first paragraph of § 112 unless there is reason to doubt the objective truth of the statements contained therein which must be relied on for enabling support." Fiers v. Revel, 984 F.2d 1164, 1171-2 (Fed. Cir. 1993) (citing in re Marzocchi, 439 F.2d 220, 223 (CCPA 1971) (emphasis original)) In addition, compliance with the enablement requirement does not require or mandate that a specific example be disclosed. The specification need not contain a working example if the invention is otherwise disclosed in such manner that one skilled in the art would be able to practice it without undue experimentation. Applicant submits that the present application provides sufficient disclosure for one of ordinary skill in the art to use the claimed methods without undue experimentation. In further support of the teachings of the present application with regard to the treatment or prophylaxis of a fungal infection, fungal septicemia, and SIRS or sepsis caused by the presence of a product derived from a fungus, and in addition to the Declaration under 37 CFR 1.132 previously made of record on April 14, 2025 ("first Soto declaration"), Applicant submits herewith a second Declaration under 37 CFR 1.132 ("second Soto declaration"). In the second Soto declaration, Dr. Francisco Lozano Soto describes the results of a fungal damage experiment to the mold Aspergillus fumigatus in the presence of the CD6-derived peptide of SEQ ID NO: 3. The results show dose dependent fungal damage to Aspergillus fumigatus in the presence of the peptide. In Dr. Francisco Lozano Soto's opinion, the results, together with those in the first Soto declaration (related to growth inhibition experiments of the fungus Cryptococcus neoformans in the presence of the peptide of SEQ ID NO: 3) suggest that the CD6-derived peptides of SEQ ID NOs: 1-3 would be capable of fungal cell wall component interactions, and would be effective in the treatment or prophylaxis of fungal infections.
Applicant respectfully submits that the first and second Soto declarations, in addition to the Vera et al. (2009) reference previously made of record (showing evidence for the binding of the CD6 soluble protein to PAMPs from fungus) support and evidence what is disclosed and made plausible by the present application disclosure in view of the knowledge of one skilled in the art at the time the application was filed, and that the present application provides a sufficient disclosure for one of ordinary skill in the art to use the claimed methods without undue experimentation.
Applicant’s arguments presented in the declaration have been considered but are not persuasive. Although the declarations (including the previous “Soto” declaration) provides inhibition data for Cryptococcus neoformans and Aspergillus fumigatus, these two organisms are not representative of the full fungal genus encompassed by the claims, which include molds, yeasts, and dimorphic fungi responsible for a wide variety of distinct infections. As stated previously, Fungi are diverse and unpredictable group that differ substantially in cell was composition, morphology, pathogenic mechanisms, immune recognition, and expression of distinct PAMPs, and they cause sepsis or SIRS via different pathways. Accordingly, activity against C. neoformans and A. Fumigatus cannot reasonably be extrapolated to the broad range of pathogenic fungi such as Candida albicans, dimorphic fungi,mucromycoses, dermatophytes and other relevant species. The record continues to lack any evidence showing that SEQ ID NO:3, or any peptide of the claims, prevents fungal infection, prevents sepsis or SIRS, or prevents any bacteria or fungal infection as required for the prophylactic portion of the claims. Likewise, no evidence is provided demonstrating neutralization of fungal toxins or PAMPs beyond the limited species tested. With respect to Applicants reliance on Vera (reference cited previously), the reference teaches that soluble CD6 protein (not the peptide fragments of the instant claims) binds to PAMPs from Schizosaccharomyces pombe, and Vera also reports that soluble CD6 failed to bind other fungal species, including C. albicans, thereby underscoring the unpredictability of fungal recognition and therapeutic response. Binding of a protein to PAMPs in a single fungal species does not establish that the claimed peptide fragments are capable of binding PAMPs from fungal species broadly or are capable of treating or preventing fungal infections as claimed. Taken together, testing only two fungal species (in light of the unpredictability of the prior art) is insufficient to eliminate the need for extensive additional experimentation across unrelated fungi to determine the efficacy required to practice the full scope of the invention. Therefore, neither declarations (Soto or “Soto 2”) demonstrate enablement commensurate with the claims and Applicants arguments that activity against C. neoformans or Aspergillus fumigatus is sufficient to support treatment or prophylaxis of all fungal infections including fungal sepsis or SIRS are not persuasive.
The Examiner further alleges that "[t]reatment of existing specific bacterial infections and one strain of fungi, does not provide enablement for treatment or prevention of any bacterial or fungal infection or any sepsis or SIRS cause[d] by said microbe or a product derived from said microbe." Office Action, page 7; emphasis added by Applicant. Applicant respectfully disagrees and submits that the pending claims are enabled by the present application. The application describes "treatment" or "therapy" as encompassing "both prophylactic and curative methods of treating disease, since both are directed to the maintenance of health" (paragraphs [0161], [0215]). The claimed subject-matter may thus be used in a method of therapeutic treatment (after the clinical manifestation of the disease) and/or prophylactic treatment (before the clinical manifestation of the disease) (paragraph [0162]). It is common general knowledge that anti-infective treatments are administered both as curative (when the infection is confirmed and/or symptomatic) and preventive, as prophylaxis to avoid the occurrence of an infection, such as before and/or during a medical intervention. Accordingly, Applicant respectfully submits that the present application provides sufficient disclosure for one of ordinary skill in the art to use the claimed methods without undue experimentation.
Applicant’s arguments have been fully considered but not found persuasive. Applicants argue that the disclosure of general “treatment” and “therapy”, including both prophylactic and curative contexts, is sufficient to enable treating or preventing any bacterial and fungal infection or sepsis caused by any bacterium or fungus. However, this argument does not address the fundamental issue that the art is highly unpredictable. Bacterial and Fungal pathogens encompass a vast number of diverse species with widely varying virulence factors, host responses, and sensitivities to peptide based therapeutics. The specification provides only limited data on a narrow set of pathogens, and does not establish that the claimed peptides would be effective (for prevention or treatment) across the full scope of infections and septic conditions recited in the claims. Thus, Applicants argument does not overcome the fact that substantial undue experimentation would be require to determine which pathogens, pathogen derived products, and septic conditions could be treated or prevented by the claimed methods.
Prior Art Made of Record
Lozano-Soto (US20140215644, cited in Applicant’s IDS). Lozano-Soto discloses a method of treating a subject (for infections, see paragraph 0088) comprising administering a composition comprising soluble human CD6 (see claims 1-2 and also SEQ ID NO:3 in claim 3). In particular, SEQ ID NO:3 (human soluble CD6) comprises instant SEQ ID NO:3. However, neither Lozano-Soto or any other prior art teaches a peptide consisting of or an 11-mer peptide comprising SEQ ID Nos:1-3 (fragments of human CD6). There is no teaching suggestion or motivation (or rationale) to make a peptide of the instant claims consisting of SEQ ID Nos:1-3 or an 11-mer peptide comprising SEQ ID Nos:1-3 and use of the fragments for treating bacterial or fungal infections with a reasonable expectation of success.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654