DETAILED ACTION
Acknowledgment and entry of the Amendment submitted on 12/26/25 is made. Claims 1-4 and 6-16 are currently pending.
Claims 6-11 remain withdrawn for being drawn to a non-elected invention.
Claims 1-4 and 12-16 are currently under examination.
Applicants’ arguments are rendered moot due to the amendments of the claims. All prior rejections have been withdrawn in view of the following rejections which were necessitated by the amendment to the claims.
Claim Rejections - 35 USC § 112-New Matter
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 1-4 and 12-16 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.
Newly amended claim 1 recites “polymeric immunoglobulin (pIgA)”; however, this term cannot be found in the original specification or claims. This is new matter. Applicant must point to written support for this language by page and line number or remove it from the claims.
Claim Rejections - 35 USC § 112-2nd paragraph
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 1-4 and 12-16 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 dependent claims thereof are vague and indefinite due to the new claim amendment which adds the phrase “an active or live mucosa-related infectious pathogen” because it is unclear what is meant by the term ‘active’. How is this different from “live”? Also, it is unclear what is encompassed by “mucosa-related infectious pathogen” accompanied with the term live and active. Are these live viruses or bacteria or something different? The claims are unclear and the metes and bounds of the invention is not readily understood. It is also unclear what is meant by the new mention of a “polymeric immunoglobulin A (pIgA)” in claim 1. There is no written description describing this. The mere recitation of a name, i.e., polymeric IgA associated with mucosal immunity; or ‘mucosa-related infectious pathogen’, to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. These terms are used for many different structures from countless sources. The mere recitation of a name does not adequately define the claimed antibody or pathogen. Further, While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow for one to identify what is being claimed. Appropriate clarification/and or correction is required.
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.
Claim(s) 1-4 and 12-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wahid et al (Clin Immunol. 2011 Feb;138(2):187–200) and Wahid et al (Wahid2) Clin Immunol. 2019 Mar 5. Vol. 201:61–69) in view of Zelenov et al (RU 2438709; Jan, 10, 2012; provided by Applicants) and Wheeler et al (WO 01/51082; provided by Applicants).
Wahid et al teaches oral vaccination with a live mucosa-related infectious pathogen, e.g., live, oral Salmonella typhi vaccine, CVD 909, or live oral Salmonella etnerica serovar Typhi vaccine Ty21a. Healthy adult volunteers (9 human males, 11 human females) were vaccinated following the routine U.S. immunization schedule for the Ty21a typhoid vaccine, i.e., four spaced doses of 2×109 to 6×109 CFU of Ty21a at an interval of 48 h between doses. Blood was collected before immunization (day 0) and on day 70, post vaccination to obtain PBMC samples. Serum IgG, IgA and IgM antibody titers to S. Typhi LPS (Difco), and H:d flagella antigen were measured by ELISA. The observations that oral immunization with the Ty21a typhoid vaccine, unlike systemic immunization with other antigens, elicits IgA ASC cells that preferentially express gut homing receptors, the major role that the GALT (Gut Associated Lymphoid Tissue) has in the production of secretory IgA and that mucosal immune responses play a key role in protection from S. Typhi, as well as other enteric pathogens support this contention. In sum, this is the first demonstration that a single oral vaccination with an attenuated S. Typhi vaccine that constitutively expresses the Vi polysaccharide (i.e., CVD 909) elicits long-term BM responses against this T-I antigen. We also report that oral immunization with Ty21a and CVD 909 generates long lasting BM responses against LPS and flagella. These observations support the notion that immunization with oral typhoid vaccines elicits a broad range of persistent effector immune responses that might play critical roles in long term protection.
Wahid et al (Wahid2) Clin Immunol. 2019 Mar 5. Vol. 201:61–69) evaluated cell mediated immune (CMI) responses elicited in volunteers following immunization with a single dose (109 or 1010 cfu) of a novel attenuated live oral PA-vaccine strain (CVD 1902).
Taken together, the data of these references by Wahid et al indicate that live oral attenuated vaccines (live/active mucosa-related infectious pathogens) can elicit antigen-specific IgA and IgG BM cell responses and T-cell-mediated immunity (T-CMI) responses following vaccination in ADULT mammals/humans.
Due to the very broad definitions in instant claims, given that S.typhi is an infectious pathogen, the live attenuated vaccines of Wahid are encompassed by this language. It is noted that the sole steps of the method include administering an active or live mucosa-related infectious pathogen to an adult mammal through an oral or nasal route. Zelenov and Wheeler are further cited to show that it was prima facie obvious to produce protective immune serum that includes sIgA as a primary antibody through oral administration of an adult mammal.
Zelenov discloses a method for producing hyperimmune serum (antibody-containing serum) by administering an antigen of a mucous membrane-related pathogen to producer oxen, i.e., adult mammal (see abstract, top of page 3 and pages 6-7); a method for preventing and treating infectious rhinotracheitis, etc. by injecting the hyperimmune serum (antibody-containing serum) into calves (see page 6 and claim 2), stating that the hyperimmune serum (antibody-containing serum) can be administered via the routes such as oral, subcutaneous, intravenous, etc., within 1-1.5 hours after birth (see pages 6 and 9). Zeleonov also teaches where the mammals may be oxen. See page 7. The abstract and page 6 discuss mucosa viruses or microbial pathogens causative of acute gastrointestinal and respiratory diseases wherein the microbial pathogens are rotavirus and cattle coronavirus. Serum contains ready antibodies against infectious rhinotracheitis viruses, parainfluenza, company, corona and diarrhea - mucosal diseases and has a preventive effect and therapeutic effect, creates passive immunity, which lasts up to three months. (see abstract and page 6). Page recites it is the "Method for producing adhesive and antitoxic serum against the escherichiosis of farm animals, which ensures the neutralization of the pathogenic effect of Escherichia in animals of various species (1). As a rule, concomitant infections occur in 75-85% of cases, and the mono-serum does not have specific activity against the rota-, corona, and herpesviruses - the main pathogens of this pathology. Polyspecific hyperimmune serum against rota-, corona, herpesvirus and E. cali (K-99, A 20) is also known for local protection and immunotherapy of mixed forms of diarrhea in newborn calves. Serum contains antibodies in titres: to rotavirus - not less than 7: 3200 (in ELISA), to coronavirus - no less than 1: 512 (in RNGA\), to herpesvirus - 1: 512 (in PH), to Escherichia having adhesin K 99 and A 20 - not less than 1: 1600 Gin RA), to the thermostable enterotoxin of E. coli - not less than 7: 4 Gin RDP). Obtained by the hyperimmunization of producer oxen with a polyvalent viral antigen containing a mixture of culture virus suspensions and inactivated E. coli antigens containing somatic, adhesive (K-99, A 20) antigens in physiological saline, anatoxins in a culture medium. Secretory IgA is the main antibody found in mucosal secretions- like saliva, breast milk, nasal fluids, tears and intestinal secretions. It plays a frontline role in mucosal immunity. It resists enzymatic breakdown in harsh mucosal environments.
Wheeler et al teach a method of producing a mucosal and systemic immune response in a human or animal comprising administering sublingually an effective amount of a composition comprising at least one antigen and a glycolipid adjuvant to said human or animal. A method of treating a mucosally transmitted disease comprising administering sublingually, i.e., orally, to a human or animal an effective amount wherein the method produces an IgA immune response. A method according to any preceding claim wherein the antigen is derived from a bacterium, virus, prion, neoplasm, autoantigen, animal, plant, recombinant or synthetic material. Preferably the composition is administered to humans, mammals and other primates, including non-human primates such as apes and monkeys, farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like (see page 6-7). Page 10, line 15-page 11, line 2 recites that the mucosal system protects the organism from antigens entering the body directly through mucosal epithelial surfaces. Thus, lymphoid tissues are found associated with surfaces lining the intestinal tract, the respiratory tract and genitourinary tract. The present invention particularly relates to lymphoid tissues found associated with surfaces lining the sublingual region. The major effector mechanism at these sites is secretory IgA (sIgA), secreted directly onto the mucosal epithelial surfaces or the tract. Secretory IgA represents over 95% of all Ig found in secretions and is primarily dimeric with two monomeric units covalently joined by a J chain. Dimeric IgA binds to a polymeric immunoglobin receptor pIGR on the basal surface of mucosal epithelial cells. This IgA-pIGR complex is endocytosed and transported to the apical (luminal) surface of the epithelial cell. During this transport process, a small piece of the pIGR is cleaved with the remaining component now called the secretory component. Thus, IgA is secreted as dimeric IgA bound to a secretory component. It is taught that the antigen may be from any living organism, viral or bacterial (see top of page 13). The reference recites, for example, micro-organisms against which vaccines are available or are sought include Salmonella, Shigella, Klebsiella, Enterobacter, Serratia, Proteus, Yersinia, Vibrio, Aeromonas, Pasteurella, Pseudomonas, Acinetobacter, Moraxella, Flavobacterium, Bordetella, Actinobacillus, Neisseria, Brucella, Haemophilus and Escherichia coli. Preferred vaccines include vaccinia (for smallpox); vole bacillus (for TB); polio; measles, mumps; rubella; yellow fever; varicella-zoster; BCG; rabies; influenza; hepatitis A; typhus; pertussis; typhoid; cholera; plague; pneumococcus; meningococcus; Haemophilus influenzae; hepatitis B; hepatitis C; tetanus and diphtheria. Toxin based vaccines include Clostridium tetani, Corynebacterium diphtheriae, Vibrio cholerae and Clostridium perfringens. Pages 13-14 recite that Other major diseases for which vaccines may be useful include: HIV, herpes, viruses, adenoviruses, rhinoviruses, staphylococci, group A _ streptococci, Mycobacterium leprae, Treponema pallidum, Chlamydia, Candida, Pneumocystis, malaria, trypanosomiasis; Chagas’ disease; schistosomiasis and onchoceriasis. Sexually transmitted diseases for which vaccines may be useful include, in addition to HIV and herpes mentioned above: Neisseria gonorrhoeae, Treponema pallidum, Trichomonas vaginalis, Haemophilus ducreyi, Chlamydia, Calymmatobacterium granulomatis and hepatitis.
The prior art cited teach that it was very well known in the prior art to produce sIgA serum with mucosal immunity capability by administering a mucosa-related infectious pathogen to a mammal through an oral or nasal route. The Wahid references teach that immunization with the live mucosa-related pathogen produces sIgA and Zelenov and Wheeler teach that the antigen, obtaining serum after administration of said antigen, presence of protective antibody providing mucosal immunity remain consistent regardless of the specific mammal or pathogen involved. These variations merely represent routine application of the inventive concept to different, but analogous, biological systems or pathogenic challenges. Wheeler further teaches that it would have been obvious that the adult mammal could be humans, mammals and other primates, including non-human primates such as apes and monkeys, farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like (see page 6-7). Wheeler teaches a method of treating a mucosally transmitted disease comprising administering sublingually, i.e., orally, to a human or animal an effective amount wherein the method produces an IgA immune response. Accordingly, it would have been prima facie obvious at the time the invention was made that the administration route of the producer oxen in the Zelenov reference could be orally or nasally (mucosally vaccinated) as is done for the calves in the reference as Wheeler teaches that doing so in an adult mammal produces secretory IgA. The instantly claimed method steps recite the active step of administering a mucosa-related infectious pathogen to an adult mammal through an oral or nasal route thereby producing a serum containing a protective antibody with mucosal immunity which includes sIgA. Wheeler teaches that secretory IgA represents over 95% of all Ig found in mucosal epithelial secretions, i.e., is the primary protective antibody raised in mucosal administration. Accordingly, given the extensive teachings of the prior art at the time the invention was made it would have been prima facie obvious to one of ordinary skill in the art to perform a method of producing serum containing protective antibody with mucosal immunity capable of protecting against mucosa-related infectious pathogen, and that sIgA would be the primary antibody.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Prior art, not presently relied upon:
Li et al (Biomed Res. Int. Jan. 3, 2020, 6 pages)
Immunoglobulin A (IgA) is the most abundant antibody isotype in the mucosal immune system. Structurally, IgA in the mucosal surface is a polymeric structure, while serum IgA is monomeric. Secretory IgA (sIgA) is one of the polymeric IgAs composed of dimeric IgA, J chain, and secretory component (SC). Most of sIgAs were generated by gut and have effects in situ. Besides the function of “immune exclusion,” a nonspecific immune role, recent studies found it also played an important role in the specific immunity and immunoregulation. Thanks to the critical role of sIgA during the mucosal immune system homeostasis between commensal microorganisms and pathogens; it has been an important field exploring the relationship between sIgA and commensal microorganisms.
Blaise Corthesy (Front Immunol. 2013 Jul 12;4:185).
Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer’s patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.
Feng et al (CN 107312088 11/3/2017 )
The title test kit includes monoclonal antibody against SIgA SC
fragment, the monoclonal antibody is produced by secretion of
microorganism hybridoma cell strain 2F9 (CGMCC No.13813), is prepd. by
using SIgA purified from colostrum as antigen, and immunizing BalB/C
mouse to obtain one hybridoma cell strain that stably secrets secretory
piece (SC) against SIgA mol., and the monoclonal antibody is applied to
establish ELISA method and test kit for detecting SIgA antibody against
porcine epidemic diarrhea virus (PEDV) with high specificity and
sensitivity. The invention provides effective technique means for further
researching specific SIgA level and mucosal immunity evaluation
after porcine is infected by PEDV and is immunized with PEDV vaccine.
De Sousa-Pereira et al (Antibodies (Basel). 2019 Dec 5;8(4): 1-30).
Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA to effective immune defense is signaled by the fact that more IgA is produced than all the other immunoglobulin classes combined. Indeed, IgA is not just the most prevalent antibody class at mucosal sites, but is also present at significant concentrations in serum. The unique structural features of the IgA heavy chain allow IgA to polymerize, resulting in mainly dimeric forms, along with some higher polymers, in secretions. Both serum IgA, which is principally monomeric, and secretory forms of IgA are capable of neutralizing and removing pathogens through a range of mechanisms, including triggering the IgA Fc receptor known as FcαRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structure–function relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena.
Melkebeek et al Veterinary Immunology and Immunopathology (2013), 152(1-2), 37-42
A review. Enterotoxigenic Escherichia coli (ETEC) remain an
important cause of neonatal and post-weaning diarrhea in pigs. In
general, neonatal infections can be prevented effectively by passive
colostral and lactogenic immunity obtained by vaccination of the sow. In
this respect, several maternal vaccines are on the market. These are
applied mainly parenterally in the pregnant sow. However at weaning,
lactogenic protection disappears. Strains involved in post-weaning
diarrhea mostly express F4 or F18 fimbriae. These fimbriae are important
virulence factors since they allow the bacteria to bind to specific
receptors on small intestinal enterocytes, resulting in colonization and
subsequently the secretion of enterotoxins causing diarrhea. Consequently,
an active mucosal immunity, in which the local prodn. of F4- and/or
F18-specific sIgA plays an important role, is required to protect
pigs against post-weaning diarrhea. Consequently, an active mucosal
immunity, in which the local prodn. of F4- and/or F18-specific sIgA
plays an important role, is required to protect pigs against
post-weaning diarrhea. This review aims to give an overview of the
immunization strategies applied in the pig model to prevent post-weaning
diarrhea caused by F4- and/or F18- pos. ETEC in pigs. These include the
use of oral live and subunit vaccines, encapsulation strategies and
parenteral immunization.
Czerkinsky et al (Immunl Rev. 170(1): 197-222. August 1999)
Abstract
Summary: The mucosal immune system of mammals consists of an integrated network of lymphoid cells which work in concert with innate host factors to promote host defense. Major mucosal effector immune mechanisms include secretory antibodies, largely of immunoglobulin A (IgA) isotype, cytotoxic T cells, as well as cytokines, chemokines and their receptors. Immunologic unresponsiveness (tolerance) is a key feature of the mucosal immune system, and deliberate vaccination or natural immunization by a mucosal route can effectively induce immune suppression. The diverse compartments located in the aerodigestive and genitourinary tracts and exocrine glands communicate via preferential homing of lymphocytes and antigen-presenting cells. Mucosal administration of antigens may result in the concomitant expression of secretory immunoglobulin A (S-IgA) antibody responses in various mucosal tissues and secretions, and under certain conditions, in the suppression of immune responses. Thus, developing formulations based on efficient delivery of selected antigens/tolerogens, cytokines and adjuvants may impact on the design of future vaccines and of specific immunotherapeutic approaches against diseases associated with untoward immune responses, such as autoimmune disorders, allergic reactions, and tissue-damaging inflammatory reactions triggered by persistent microorganisms.
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/JENNIFER E GRASER/Primary Examiner
Art Unit 1645 3/18/26