DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/5/25 has been entered.
Claims 1, 3, 6, 7, 16, 22, 25, 28, 30, 35, 38, 48 and 130 (Species: S. epidermis and ovalbumin) are currently under examination.
Claims 41, 43, 51, 52, 78, 98 and 104 remain withdrawn from consideration for being drawn to a non-elected invention pursuant to 37 CFR 1.142(b).
The former rejections under 35 USC 102 have been withdrawn.
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, 3, 6, 7,16, 18, 22, 25, 28, 30, 35, 38, 48 and 130 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (FEMS Microbiology Letters. 2006, 265(2): 225-236), Dubensky et al (US 2005/0249748), Lasse et al (Applied and Environ. Microbiol. 76(21): 7359-7362. Nov. 2010; provided by applicants) and Jaffee et al (US2017072040) in view of Munivar et al (WO 2015/184134; provided by Applicants) and Whitfill, T. (WO 2019/050898; provided by Applicants).
Lee et al disclose a live, recombinant commensal bacterium, wherein the bacterium is engineered to express a non-native protein (Abstract, "we engineered Streptococcus gordonii to express a 26 kDa fragment of cyst wall protein 2 (CWP2), containing a relevant B cell epitope, on the cell surface. This is the first report of S. gordonii expressing a protein of parasite origin"), - wherein the protein is associated with a host disease or condition (Abstract, "Giardia lamblia (Giardia duodenalis or Giardia intestinalis) is a protozoan parasite of vertebrates with broad host specificity. Specific antibodies directed against cyst antigens can interfere with the cyst wall-building process”), - wherein upon administration of the bacterium to the host resulting in colonization of a native host niche by the bacterium (Abstract, "As S. gordonii was intended for intestinal delivery of CWP2, it was determined that this oral commensal bacterium is able to persist in the murine intestine for 30 days"), - wherein the host mounts an adaptive immune response to the non-native protein or peptide (Abstract, "Immunization with recombinant streptococci expressing the 26 kDa fragment resulted in higher antibody levels. Specific anti-CWP2 IgA antibodies were detected in fecal samples and anti-CWP2 IgG antibodies were detected in serum demonstrating the efficacy of S. gordonii for intragastric antigen delivery. In a pilot challenge experiment, immunized mice demonstrated a significant 70% reduction in cyst output"). Lee does not specifically disclose that the adaptive immune response is a regulatory T-cell (Treg) response or an effector T-cell (Teffector) response. However, said limitation is met by/inherently present in Lee as follows: Lee discloses that "[s]pecific anti-CWP2 IgA antibodies were detected in fecal samples and anti-CWP2 IgG antibodies were detected in serum demonstrating the efficacy of S. gordonii for intragastric antigen delivery” (Abstract) and that immunized mice produces neutralizing antibodies (Abstract, "immunized mice demonstrated a significant 70% reduction in cyst output"). A paper entitled “Host defences against Giardia lamblia" by Lopez-Romero, et al. (hereinafter "Lopez-Romero") discloses that "IgA and CD4+ T cells are fundamental to the process of Giardia clearance. It has been suggested that CD4+ T cells play a double role during the anti-Giardia immune response. First, they activate and stimulate the differentiation of B cells to generate Giardia-specific antibodies. Second, they act through a B-cell-independent mechanism that is probably mediated by Th17 cells" (Abstract), and "that when mice were immunized with CWP2, the production of anti-Giardia lgA and 1gG2a was induced” (pg 402, col 1). Since Lee discloses that “[s]pecific anti-CWP2 IgA antibodies were detected in fecal samples and anti-CWP2 IgG antibodies were detected in serum demonstrating the efficacy of S. gordonii for intragastric antigen delivery" (Abstract) and Lopez-Romero discloses "that when mice were immunized with CWP2, the production of anti-Giardia IgA and IgG2a was induced” (pg 402, col 1), it follows then that the adaptive immune response disclosed by Lee is a regulatory T-cell (Treg) response or an effector T-cell (Teffector) response. Lee discloses that the native host niche is transiently colonized for about 28 days (Abstract, "S. gordonii... is able to persist in the murine intestine for 30 days").
Dubensky et al disclose a live, recombinant commensal bacterium (a bacterium selected from the group consisting of... Bacillus...£. coli, Para. [0100)) engineered to express a fusion protein (comprising a polynucleotide encoding a signal peptide and a second polynucleotide encoding a polypeptide, Para. [0100]), the fusion protein comprising: (a) a non-native protein or peptide (a second polynucleotide encoding a polypeptide...an antigen, Para. [0100]), and (b) a tat signal sequence peptide, a sec signal sequence peptide, a sortase-derived signal sequence peptide, and/or an antigen-presenting cell (APC) targeting moiety, (the signal peptide is a tat signal peptide, Para. [0100]) wherein administration of the bacterium to the host results in colonization of a native host niche by the bacterium (wherein the bacteria are administered orally, Para. (0341]), and generation of an adaptive immune response by the host against the non-native protein or peptide (using the bacteria or compositions comprising the bacteria to induce an immune response and/or to prevent or treat a condition (e.g., a disease) in a host, Para. [0100)). Further, regarding the limitation relating to “wherein administration of the bacterium to the host results in colonization of a native host niche by the bacterium, and generation of an adaptive immune response by the host against the non-native protein or peptide (and the dependent claim limitations of treating host diseases, autoimmune disorders and cancers)," a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, it meets the limitation for “wherein administration of the bacterium to the host results in colonization of a native host niche by the bacterium, and generation of an adaptive immune response by the host against the non-native protein or peptide”. Dubensky discloses the live, recombinant the non-native protein or peptide is associated with a host disease or condition selected from the group consisting of: (i) a cancer; (ii) an autoimmune disorder; and (iii) an infection that occurs at or is otherwise associated with a mucosal boundary of the host (the polypeptide encoded by the second polynucleotide comprises an antigen, wherein the antigen is tumor-associated antigen or is derived from a tumor-associated antigen, infectious disease antigen or is derived from an infectious disease antigen, Para. (0100). Dubensky discloses wherein the signal sequence peptide: (i) directs tethering of the expressed fusion protein to a cell wall of the bacterium; or (ii) directs secretion of the fusion protein from the bacterium following expression (the signal peptide sequence in an expression cassette enhances the expression and/or secretion of a heterologous polypeptide (such as an antigen) from recombinant bacteria, Para. (0095)). Dubensky discloses a method of treating a disease or condition in a subject (Methods of using the bacteria or compositions comprising the bacteria to induce an immune response and/or to prevent or treat a condition... in a host are also provided. In some embodiment, the condition is cancer. In other embodiments, the condition is an infectious disease, Para. [0100]) comprising: administering a live, recombinant commensal bacterium engineered to express a heterologous antigen to a subject (a bacterium selected from the group consisting of...Bacillus...E. coli, Para. (0100); comprising a polynucleotide encoding a signal peptide and a second polynucleotide encoding a polypeptide...an antigen, Para. [0100]; wherein the bacteria are administered orally, Para. [0341]), wherein the expressed heterologous antigen induces an antigen-specific immune response to treat the disease or condition in the subject (for inducing an immune response in a host to an antigen, wherein the polypeptide encoded by the second polynucleotide comprises the antigen is... provided, Para. [0100)). It is noted that the instant claims are drawn to a product: a recombinant transformed bacteria so intended use, e.g, the host mounts an adaptive immune response to the non-native peptide or protein…, is an intended use only.
Lasse et al shows the commensal bacterium L. plantarum WCFS1 from human saliva isolate expressing mammalian tumor immunogen termed onco-fetal antigen (OFA). Therein, OFA was either secreted from the bacteria or anchored to the bacterial wall. The oral administration of OFA-expressing L. plantarum induced a specific immune response against OFA in mice as detected by the presence of OFA-specific IgG (abstract, Fig 3). It is noted that the instant claims are drawn to a product: a recombinant transformed bacteria so intended use, e.g, the host mounts an adaptive immune response to the non-native peptide or protein…, is an intended use only.
Jaffee et al is related to an antigen-specific vaccine approach to induce an immune response, and in particular a CD4+ T cell response against tumor antigen (par. 5, 7}. The document discloses that commensal microorganisms such as S. gordonii, Lactobacillus spp. and Staphylococcus spp. can be used as carriers for said vaccine strategy, inducing of an immune response towards a human/murine antigen (par. 70-79}. A method to induce a CD8+ or CD4+ F cell response to a pancreatic tumor by administering E. coli bacteria expressing mesothelin as the carrier (wherein the carrier is selected from a group of three alternatives) is disclosed (par. 64, 68, claims 5-12). Pharmaceutical compositions are disclosed (par. 96). The features “resulting in persistent or transient colonization” has to be assumed as an inherent feature exhibited by any commensal bacteria. The features “internalization of the bacterium by an antigen-presenting cell, and presentation of the antigen by the antigen-presenting cell" and "generation of a T-cell response, wherein the T-cell response is of an antigen derived from the non-native mammalian host protein or peptide, and wherein the T-cell response treats the disease or condition in the subject") can be regarded as inherent functional features of a pharmaceutical composition which induces an effector/regulatory T cell response
The teachings of Lee, Dubensky, Lasse, and Jaffee all demonstrate the use of live, commensal bacteria as good options to express a protein antigen or peptide antigen associated with a host disease or condition to result in persistent or transient colonization of a native host niche by the bacterium so that the host mounts a T cell response to the peptide antigen. Although Jaffee does disclose that commensal microorganisms such as S. gordonii, Lactobacillus spp. and Staphylococcus spp. can be used as carriers for said vaccine strategy, the reference does not specifically recite the Staphylococcus species to be S. epidermidis. Lee, Dubensky, Lasse and Jaffee all teach live, commensal bacteria as efficient host cells for the same purposes of raising an effective immune response, more particularly a Tcell response, in a host.
Munivar et al teaches a live recombinant commensal bacterium engineered to produce a recombinant polypeptide for therapeutic treatment of an abnormal skin condition. Pharmaceutical compositions comprising the bacterium expressing the recombinant therapeutic polypeptide are also taught. See abstract. Figures 1-8 describe the transformation of S. epidermidis cells. The recited features “resulting in persistent or transient colonization” has to be assumed as an inherent feature exhibited by any commensal bacteria. The features “internalization of the bacterium by an antigen-presenting cell, and presentation of the antigen by the antigen-presenting cell" and "generation of a T-cell response, wherein the T-cell response is of an antigen derived from the non-native mammalian host protein or peptide, and wherein the T-cell response treats the disease or condition in the subject") can be regarded as inherent functional features of a pharmaceutical composition since the bacterium of Munivar is structurally identical to that of claim 1. A recitation of the intended use of the claimed invention (recombinant bacteria) must result in a structural difference between the claimed invention and the prior art in order to distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, it meets the limitation for “wherein administration of the bacterium to the host results in colonization of a native host niche by the bacterium, and generation of an adaptive immune response by the host against the non-native protein or peptide. The instant claims are drawn to a product not a method. Dependent claims 3, 6, 7,16, 18, 22, 25, 28, 30, 35, 38, 48 and 130 recite functions or “intended” administration. However, the claims are drawn to a product.
Whitfill recites recombinant microorganisms for the treatment of an inflammatory skin condition. Lines 14-26, on page 2 of the reference recite that engineered probiotics are a novel approach based on leveraging the skin microbiome for therapeutic purposes. Notably, an engineered probiotic has important advantages over other methods of drug delivery, as it will establish residence on the patient’s skin and continuously and stably deliver therapeutic proteins in situ. Furthermore, certain strains of Staphylococcus epidermidis (SE) have demonstrated important beneficial immuno- modulatory and anti-pathogen effects in the skin, which are relevant to atopic dermatitis disease phenotype and severity. Moreover, the delivery of filaggrin, which is a structural protein derived from profilaggrin, further enhances the therapeutic approach due to filaggrin’s role in the skin barrier and ability to reduce transepidermal water loss and improve skin hydration. The present invention has the surprising advantage of providing methods and compositions for treating skin diseases, e.g., atopic dermatitis, using a genetically engineered, recombinant strain of Staphylococcus epidermidis as a skin drug delivery system that secretes human filaggrin to address the pathophysiology of atopic dermatitis (e.g., AZT-01). Whitfill teaches a method for producing a live biotherapeutic composition, the method comprising (a) transfecting a cell with (i) a first coding sequence comprising a nucleic acid sequence capable of expressing a therapeutic polypeptide, and (ii) a second coding sequence comprising a nucleic acid sequence capable of expressing a cell penetrating peptide; and (b) allowing the transfected cell to produce a therapeutic polypeptide fusion protein; and (c) obtaining the live biotherapeutic composition. In a related embodiment, the method further comprises (iii) transfecting the cell with a third coding sequence comprising a nucleic acid sequence capable of expressing an export signal. In another embodiment, the first coding sequence, second coding sequence and third coding sequences are arranged in a single plasmid. In yet another embodiment, the arrangement of the first coding sequence, second coding sequence and third coding sequences are operably linked to a promoter. In other embodiments, the cell is selected from the group consisting of wherein the microorganism is selected from the group consisting of Bifidobacterium, Brevibacterium, Propionibacterium, Lactococcus, Streptococcus, Staphylococcus, Lactobacillus, Enterococcus, Pediococcus, Leuconostoc, or Oenococcus, or combinations thereof. In yet another embodiment, the cell is Staphylococcus epidermidis. See page 4, lines 18-33. Page 12 recites that in certain embodiments of the invention, the bacterium is Staphylococcus epidermidis. In preferred embodiments of the invention, the strain of S. epidermidis to be used is incapable of producing biofilms. One such example of a strain of S. epidermidis incapable of producing biofilms is S. epidermidis strain ATCC 12228. However, in yet other embodiments of the invention, other related or similar species found on the skin can be used.
The teachings of Lee, Dubensky, Lasse, and Jaffee all demonstrate the use of live, commensal bacteria as good options to express a protein antigen or peptide antigen associated with a host disease or condition to result in persistent or transient colonization of host by the bacterium so that the host mounts a T cell response to the peptide antigen. The references show that many different types of live, commensal bacteria are useful and successful for this purpose, with Jaffee specifically referencing Staphylococcus spp. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the live, commensal S. epidermidis host cell of Munivar or Whitfill to express any of the polypeptides disclosed in the secondary references and be used to treat a variety of different pathogenic conditions, cancers and other diseases as a mere design choice. All of the references teach the use of ‘commensal’ bacterium, some of which teach Staphylococcus spp., to accomplish this and it is taught that a variety of different bacteria may be used as the host cell. Whitfill and Munivar have established S. epidermidis as good commensal host cell to express a protein. This coupled with the teachings of the secondary references that that commensal microorganisms such as S. gordonii, Lactobacillus spp. and Staphylococcus spp. can be used as carriers for a vaccine strategy, inducing of an immune response towards a human/murine antigen. Dubensky discloses the live, recombinant the non-native protein or peptide is associated with a host disease or condition selected from the group consisting of: (i) a cancer; (ii) an autoimmune disorder; and (iii) an infection that occurs at or is otherwise associated with a mucosal boundary of the host (the polypeptide encoded by the second polynucleotide comprises an antigen, wherein the antigen is tumor-associated antigen or is derived from a tumor-associated antigen, infectious disease antigen or is derived from an infectious disease antigen, Para. (0100).
Response to Applicants’ arguments:
Applicants argue that :
Munivar and Whitfill do not teach the use of commensal bacteria to express all kinds of different polypeptides for a vast variety of diseases and conditions (emphasis added). Instead, both Munivar and Whitfill teach the use of commensal bacteria to express a specific polypeptide (e.g., filaggrin) for the treatment of a specific disease of AD and the delivery of filaggrin to the skin as that treatment (emphasis added). As disclosed above, filaggrin is not an antigen. A prior art reference must be considered in its entirety, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Considering Munivar and Whitfill as a whole, since AD is an inflammatory disease, one skilled in the art would not look to modify Munivar and Whitfill express an antigen, as an antigen would further exacerbate the inflammatory disease of AD. Furthermore, any of Lee, Dubensky, Lasse, and Jaffee fail to make up for the deficiencies of Munivar and Whitfill. Both Munivar and Whitfill teach away from the expression of a protein antigen or peptide antigen. Munivar and Whitfill are attempting to treat a chronic inflammatory disease by continually supplying a polypeptide that either directly or indirectly reduces the inflammation. The application of an antigen to a chronic inflammatory environment would exacerbate the very condition of AD that Munivar and Whitfill are trying to treat. For that reason, one skilled in the art would not look modify Munivar and/or Whitfill in view of any one of Lee, Dubensky, Lasse, and Jaffee.
These arguments have been fully and carefully considered but are not deemed persuasive. The Examiner makes note that the order of the references in the 103-rejection recited above has been changed in this non-final office action with Munivar and Whitfill now being used as the secondary references.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The teachings of Lee, Dubensky, Lasse, and Jaffee all demonstrate the use of live, commensal bacteria as good options to express a protein antigen or peptide antigen associated with a host disease or condition to result in persistent or transient colonization of host by the bacterium so that the host mounts a T cell response to the peptide antigen. The references show that many different types of live, commensal bacteria are useful and successful for this purpose, with Jaffee specifically referencing Staphylococcus spp. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the live, commensal S. epidermidis host cell of Munivar or Whitfill to express any of the polypeptides disclosed in the secondary references and be used to treat a variety of different pathogenic conditions, cancers and other diseases as a mere design choice. All of the references teach the use of ‘commensal’ bacterium, some of which teach Staphylococcus spp., to accomplish this and it is taught that a variety of different bacteria may be used as the host cell. Whitfill and Munivar have established S. epidermidis as good commensal host cell to express a protein. This coupled with the teachings of the secondary references that that commensal microorganisms such as S. gordonii, Lactobacillus spp. and Staphylococcus spp. can be used as carriers for a vaccine strategy, inducing of an immune response towards a human/murine antigen. Dubensky discloses the live, recombinant the non-native protein or peptide is associated with a host disease or condition selected from the group consisting of: (i) a cancer; (ii) an autoimmune disorder; and (iii) an infection that occurs at or is otherwise associated with a mucosal boundary of the host (the polypeptide encoded by the second polynucleotide comprises an antigen, wherein the antigen is tumor-associated antigen or is derived from a tumor-associated antigen, infectious disease antigen or is derived from an infectious disease antigen, Para. (0100).
Claim Rejections - 35 USC § 112-Scope of Enablement
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, 3, 6, 7,16, 18, 22, 25, 28, 30, 35, 38, 48 and 130 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: a live recombinant S. epidermidis engineered to express PMEL antigen and recombinant S. epidermidis engineered to express OVA +/- luciferase and also wherein the condition is a cancer selected from melanoma, basal cell carcinoma and squamous cell carcinoma , does not reasonably provide enablement for claim 1 the full breadth of the claims which allow for any peptide/protein antigen for treating a vast number of completely different diseases and or/conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Newly amended claim 1 recites:
1. (Currently Amended) A live, recombinant Staphylococcus epidermidis commensal bacterium, wherein the bacterium is engineered to express a protein antigen or peptide antigen, wherein the protein antigen or peptide antigen is associated with a host disease or condition, wherein upon administration of the bacterium to a mammalian host resulting in persistent or transient colonization of a native host niche by the bacterium, the host mounts an adaptive immune response to the protein antigen or peptide antigen, wherein the adaptive immune response is a regulatory T-cell (Treg) response or an effector T-cell.
The claims recite a live, recombinant commensal S. epidermidis bacterium recombinantly expressing a non-native mammalian host protein with the intended use being: upon administration will result in Teff activation towards the mammalian host protein which will treat a very large laundry list of host diseases, conditions, autoimmune disorders with the use of a extremely large laundry list of peptides and proteins. The description provides in vivo data for recombinant bacteria expressing a self-antigen, which mounts a tolerogenic immune response via Treg cell induction. The only in vivo data was shown for recombinant bacteria expressing a non-mammalian antigen (OVA) and no T cell activation data was provided, neither for Treg nor for Teff cells. The objection being further corroborated by the fact that only a vague figure legend and no explication on the experimental design has been provided in the application. With respect to the administered bacteria to the mammalian host resulting in (...] colonization of a native host niche by the bacterium, the application does not sufficiently disclose the administration method which would in fact result in colonization as claimed. The application only shows oral inoculation with bacteria, or a topical application of bacteria on the skin - albeit in the latter case for a bacterium expressing a non-mammalian protein. However, no data was provided to show that these application methods in fact do result in the colonization of a host niche. The description only provides in vivo data for oral inoculation of mice with the gut-resident bacteria B. vulgatus and B. finegoldii (expressing a self-antigen) resulting in Treg cell induction. Hence, support and disclosure can only be acknowledged for the alleged Treg induction in the gut upon colonization with gut-resident commensal bacteria expressing a self-antigen derived from the host.
The only description and working examples for the use of S. epidermidis as the host commensal bacteria is in Figures 8-10 and paragraphs 42-44. These passages teach a S. epidermidis engineered to express PMEL antigen and recombinant S. epidermidis engineered to express OVA +/- luciferase either 2 week before or 1 week after subcutaneous or intraperitoneal injection of melanoma cells.
However, the ability of the bacterium to mount a regulatory response via colonization of any native host niche and the breadth of the peptides/proteins and host conditions/diseases/disorders as claimed is not supported and not sufficiently disclosed. The application does not provide any data on whether any other host niche would provide a suitable micro-environment to support Treg induction. Nor does it show whether any of the claimed bacterial species would support that process. It is noted that many of the proteins or peptides are unclear and the specification does not enable one skilled in the art to identify from the very long laundry list of peptides/proteins and host diseases and conditions, including hypothetical proteins (see claim 30, for example) without an actual structure or function recited in the specification.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
In conclusion, it would be an undue burden on the skilled person to test all possible variations mammalian proteins and niches in order to arrive at symbiotic bacteria having the desired properties and treatment of the vast number of different diseases and conditions in the dependent claims. The claims have thus not been sufficiently disclosed for the skilled person to carry out the invention over the entire scope without undue burden and inventive skill.
Response to Applicants’ arguments:
Applicants argue:
The question is therefore whether Staphylococcus epidermidis is technically supported and enabled by the application as filed. In this regard, Applicants point to paragraphs [0042] to [0044] and in FIGS. 8-10 in the application as filed. Paragraphs [0042] to [0044] of the application as filed describe the following: FIG. 8 relates to expression of ovalbumin in Staphylococcus epidermidis and its use in activation of T-cells; FIG. 9 relates to expression of the cancer antigen PMEL in Staphylococcus epidermidis and its use in activation of T-cells; and FIG. 10 shows that tumor weights can be reduced in vivo by triggering an immune response to the tumor using Staphylococcus epidermidis. The data presented in FIGS. 8-9 show CD8+ and CD4+ T cell activation in vitro, by recombinant Staphylococcus epidermidis engineered to express OVA peptide or PMEL antigen (e.g., a protein antigen or peptide antigen). These data therefore demonstrate that Staphylococcus epidermidis can express different heterologous proteins and stimulate T cells against those different heterologous proteins. The experiments in FIG. 10 involve the introduction of tumor cells modified to express ovalbumin in mice (e.g., a mammalian host). Tumor weight is measured after a certain time frame, with Staphylococcus epidermidis expressing ovalbumin provided either before (left portion of FIG. 10A) or after (right portion of FIG. 10A) after introduction of the tumor cells into the mouse. This simulates prophylactic effects as well as cancer treatment, respectively, and in both cases shows that Staphylococcus epidermidis expressing ovalbumin was effective in vivo to stimulate an immune response that kills cancer cells. While ovalbumin is used in the experiment of FIG. 10, there is no reason, based on the data in the application or on the record, to expect the method would not work in vivo using other tumor antigens or indeed other protein or peptide antigens (emphasis added). FIGS. 8-9 show that the same fundamental mechanism -stimulation of T cells — is provided by expression of different heterologous proteins by Staphylococcus epidermidis. FIG. 10 therefore demonstrates that Staphylococcus epidermidis can present an antigen to a mammal and induce an immune response that is sufficient in vivo to have a therapeutically- relevant effect — here, the reduction of the size of a tumor that expresses the antigen. This provides technical support and enablement for the claimed subject-matter. Applicant respectfully requests withdrawal of the rejection.
These arguments have been fully and carefully considered.
FIG. 8 relates to expression of ovalbumin in Staphylococcus epidermidis and its use in activation of T-cells; FIG. 9 relates to expression of the cancer antigen PMEL in Staphylococcus epidermidis and its use in activation of T-cells; and FIG. 10 shows that tumor weights can be reduced in vivo by triggering an immune response to the tumor using Staphylococcus epidermidis. The data presented in FIGS. 8-9 show CD8+ and CD4+ T cell activation in vitro, by recombinant Staphylococcus epidermidis engineered to express OVA peptide or PMEL antigen (e.g., a protein antigen or peptide antigen).
This is enabled, e.g., PMEL and OVA. However, the instant claims are very broad and they include the names of hundreds of diseases and conditions and peptides/proteins, some which haven’t even been characterized and are unclear, e.g., even hypothetical proteins are also included, and Applicants arguments are not commensurate in scope to the claimed invention.
See the instant claims:
Claim 27….wherein the host disease or condition is an autoimmune disorder selected from the group consisting of multiple sclerosis, diabetes mellitus Type |, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, celiac disease, Graves’ disease, Hashimoto’s autoimmune thyroiditis, vitiligo, rheumatic fever, pernicious anemia/atrophic gastritis, alopecia areata, immune thrombocytopenic purpura, temporal arteritis, ulcerative colitis, Crohn’s disease, scleroderma, antiphospholipid syndrome, autoimmune hepatitis type 1, primary biliary cirrhosis, Sjogren’s syndrome, Addison’s disease, dermatitis herpetiformis, Kawasaki disease, sympathetic ophthalmia, HLA-B27 associated acute anterior uveitis, primary sclerosing cholangitis, discoid lupus erythematosus, polyarteritis nodosa, CREST Syndrome, myasthenia gravis, polymyositis/dermatomyositis, Still’s disease, autoimmune hepatitis type 2, Wegener’s granulomatosis, mixed Connective tissue disease, microscopic polyangiitis, autoimmune polyglandular syndrome, Felty’s syndrome, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre Syndrome, Behcet disease, autoimmune neutropenia, bullous pemphigoid, essential mixed cryoglobulinemia, linear morphea, autoimmune polyglandular syndrome 1 (APECED), acquired hemophilia A, Batten disease/neuronal ceroid lipofuscinoses, autoimmune pancreatitis, Hashimoto’s encephalopathy, Goodpasture’s disease, pemphigus vulgaris, autoimmune disseminated encephalomyelitis, relapsing polychondritis, Takayasu arteritis, Churg-Strauss syndrome, epidermolysis bullosa acquisita, cicatricial pemphigoid, pemphigus foliaceus, autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune oophoritis, autoimmune orchitis, autoimmune polyglandular syndrome, Cogan’s syndrome, encephalitis lethartica, erythema elevatum diutinum, Evans syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), Issac’s syndrome/acquired neuromyotonia, Miller Fisher syndrome, Morvan’s syndrome, PANDAS, POEMS syndrome, Rasmussen’s encephalitis, stiff-person syndrome, Vogt-Koyanagi-Harada syndrome, neuromyelitis optica, graft vs host disease, and autoimmune uveitis.
Claim 28. (Previously Presented) The recombinant commensal bacterium of claim 1, wherein the protein antigen or peptide antigen is selected from the group consisting of myelin oligodendrocyte glycoprotein, insulin, ovalbumin, chromogranin A, hybrid insulin peptides, proteolipid protein, myelin basic protein, villin, epithelial cellular adhesion molecule, collagen alpha-1, aggrecan core protein, 60kDa chaperonin 2, vimentin, aloha-enolase, fibrinogen alpha chain, fibrinogen beta chain, chitinase-3-like protein, (0kDa mitochondrial heat shock protein, matrix metalloproteinase-16, thyroid peroxidase, thyrotropin receptor, thyroglobulin, gluten, TSHR protein, glutamate decarboxylase 2, receptor-type tyrosine-protein phosphatase-like N, glucose-6-phosphatase 2, insulin isoform 2, zinc transporter 8, glutamate decarboxylase 1, GAD65, UniProt:A2RGMO0, integrin alpha-lib, integrin beta-3, EBV DNA polymerase catalytic subunit, 2’3’-cyclic-nucleotide 3’ phosphodiesterase, myelin associated oligodendrocyte basic protein, small nuclear ribonucleoprotein, U1 small nuclear ribonucleoprotein, histone H2B, histone H2A, histone H3.2, beta-2-glycoprotein, histone H4, 60S ribosomal protein L7, TNF- aloha, myeloperoxidase, Cbir1, MS4A12, DNA topoisomerase, CYP2D6, O-phosphoseryl-tRNA selenium transferase, pyruvate dehydrogenase complex, spectrin alpha chain, steroid 21- hydroxylase, acetylcholine receptor, MMP-16, keratin associated proteins. Chondroitin sulfate proteoglycan 4, myeloblastin, U1 small nuclear ribonucleoprotein 70 kDa, blood group Rh(D), blood group Rh(CE), myelin P2 protein, peripheral myelin protein 22, myelin protein PO, S- arrestin, collagen Alpha-1, coagulation factor VIII, collagen alpha-3(IV), desmoglein-3, desmoglein-1, Insulin-2, major DNA-binding protein, tyrosinase, 5,6-dihydroxyindole-2- carboxylic acid oxidase, HLA-A2, aquaporin-4, myelin proteolipid protein, ABC transporter, HLA | B-27 alpha chain, HLA | B-7 alpha chain, and retinol-binding protein 3.
Claim 30. (Previously Presented) The recombinant commensal bacterium of claim 1, wherein the bacterium is engineered to secrete the expressed protein antigen or peptide antigen; or engineered to express a fusion protein comprising the protein antigen or peptide antigen fused to the N-terminus or the C-terminus of a native bacterial protein or portion thereof selected from the group consisting of sialidase, anti-sigma factor, endonuclease, secreted endoglycosidase, thiol peroxidase, hypothetical protein BT_2621, hypothetical protein BT_ 3223, peptidase, Icc family phosphohydrolase, exo-poly-alpha-D-galacturonosidase, and hypothetical protein BT_ 4428.
38. (Previously Presented) The recombinant commensal bacterium of claim 1, wherein the host disease or condition is a proliferative disorder and wherein the proliferative disorder is a cancer selected from melanoma, basal cell carcinoma, squamous cell carcinoma, and testicular cancer.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
Prior art not presently relied upon:
Monk et al (“Transforming the Untransformable: Application of Direct Transformation To Manipulate Genetically Staphylococcus aureus and Staphylococcus epidermidis” mBio Volume 3 Issue 2 e00277-11, March/April 2012, pages 1-11).
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