DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 10-21 are pending and under consideration in this office action.
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 Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(1) Claims 1-10 and 15-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/009955 A1, Chavez et al., published January 22, 2015, IDS and US Pat. No., 5,716,804, Moore et al., when taken with Iyer et al., Crit Rev Immunol. 2012 ; 32(1): 23–63; Author Manuscript, pages 1-43.
Regarding claims 1 and 20, Chavez teaches a method for treating inflammation in a subject comprising expressing from one or more bacterial or viral vectors interleukin 10 (IL-10) peptide in antigen-presenting cells in the subject (Abstract; p. 2, ¶6-7; p. 3, ¶9). Chavez teaches that the adjuvant is used to increase the efficacy of therapeutic IL-10 anti-inflammatory compound by enhancing the uptake in macrophages (p. 2, ¶25; p. 19, ¶71).
Regarding claim 2, Chavez teaches that the DNA can include peptides that comprise mutations in the hinge region (p. 12, ¶52).
Regarding claims 3-4, Chavez further teaches that the mutant rat or human IL-10 proteins can have a phenylalanine at position 129 of the wild type sequence has been replaced with a serine residue, threonine, alanine or cysteine (p. 12, ¶52).
Regarding claims 5, 9, 10, and 21, Chavez teaches that the vector can comprise multiple sequences and that the vector can comprise an IRES (p. 13, ¶55). Thus, Chavez provides the requisite teachings to express multiple sequences from a single vector; and further, it would have been obvious to an artisan of ordinary skill to experiment with a vector in which the IL-10 and IL-10RI coding sequences are transcribed as a single mRNA, wherein the IRES is between the IL-10 and the IL-10RI coding sequences, because the IRES taught by Chavez is commonly known in the art to allow multiple polypeptides to be translated in eukaryotic cells from a single RNA transcript, by allowing translation to occur from both the 5'end of the message and the internal site that follows the first translated sequence, thus simplifying the vector and promoter sequences and producing both peptides in the cell.
Regarding claims 6-8, Chavez teaches expressing the peptide from a viral vector (Abstract; p. 9, ¶43); an adeno-associated virus vector (p. 9, ¶43) or a lentiviral vector (p. 9,¶43; p. 15, ¶59).
Regarding claim 15, Chavez teaches that inflammation is located in a joint (Abstract), and the one or more vectors are delivered by intra-articular injection (p. 4, ¶14; p. 10, ¶48; p. 25, ¶86).
Regarding claim 16, Chavez teaches wherein the inflammation is caused by proinflammatory cytokines or proteins produced by nerves, neurons, i.e., neuroinflammation (p. 6, ¶26).
Regarding claim 17, Chavez further teaches wherein the antigen-presenting cells are macrophages (p. 6, ¶25; p. 19, ¶71).
Regarding claims 18-19, Chavez teaches wherein the antigen-presenting cells are stably transformed with the at least one vector, and the vectors can be introduced ex vivo to treat joint inflammation using syngeneic cells (¶72). Thus given this teaching, it would obvious to stably transduce the APCs in vitro and stably maintain them in order to have a supply of stably transduced antigen-presenting cells for therapeutic purposes.
Chavez does not explicitly teach that the vector further expresses an interleukin 10 type 1 receptor (IL-10R1) peptide as required by claims 1 and 20.
However, prior to the effective date of the claimed invention, Moore teaches therapeutic IL 10 receptor and expression vectors (col 3, lines 66-67 - col 4, lines 1-2; col 3, lines 10-12) and IL-10 peptides (col 5, lines 28-30; col 9, lines 45-62), that may be used for treating inflammatory (e.g. autoimmune) conditions (col 8, lines 30-36).
Neither Chavez nor Moore specifically teach that the vector comprises both an IL-10 peptide and IL-10R1 peptide.
However, prior to the effective filing date of the instant invention, an anti-inflammatory response is mediated by 3 components, IL-10, IL-10R1 and APCs, as taught by Iyer. In particular, Iyer teaches that IL-10 immunosuppressive activity is mediated by heterodimeric IL-10 receptor (IL-10R1, IL-10R2) and that antigen presenting cells such as monocytes and macrophages appear to be the primary target of Il-10 (p. 2, ¶2). Iyer teaches that, Antigen-presenting cells (APCs) are an important source of IL-10 that serves to provide autocrine feedback to limit or resolve pro-inflammatory molecule production, restrict antigen presentation itself, enhance scavenger and phagocytic capabilities, and influence the development of adaptive responses.” See p. 17, C. Innate Immune Cells. Further, Iyer teaches that Il-10 expression is subject to feedback signaling modules that serve to dampen early expression and amplify later expression relative to the composite temporal inflammatory gene profile (p. 17, ¶2). Accordingly, Chavez and Moore provide the requisite teachings regarding the expression of IL-10 and IL-10R in cells to treat inflammation using APCs, and both references provide guidance for expression of multiple transcripts in a single vector; Iyer teaches that Il-10’s activity is a feedback mechanism that involves IL-10, IL-10R1 and APCs. Thus, it would be obvious to the skilled artisan to modify the teachings of Chavez and Moore, and co-express IL-10 and IL-10R1 in an APC to elicit an anti-inflammatory response, limit or resolve pro-inflammatory molecule production, and restrict antigen presentation.
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
(2) Claim 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/009955 A1, Chavez et al., published January 22, 2015, IDS and US Pat. No., 5,716,804, Moore et al., when taken with Iyer et al., Crit Rev Immunol. 2012 ; 32(1): 23–63; Author Manuscript, pages 1-43, as applied to claims 1-10, 15-19 above, and further in view of US 2012/0058102 A1, Wilson et al., IDS.
Chavez, Moore and Iyer are summarized and relied upon as detailed above. However, they fail to teach that the vector further comprises a self-cleaving 2A peptide as required by claim 11.
However, prior to the effective date of the instant invention, Wilson teaches a AAV vector system for delivering therapeutic products and further teaches including a self-cleaving 2a peptide between two coding sequences of interest that allows co-expression of heterologous gene products by a message from a single promoter when the transgene is large, consists of multi-subunits, or two transgenes are co-delivered. See ¶58.
Accordingly, it would have been obvious to the skilled artisan to modify the teachings of Chavez, Moore and Iyer, and include a self-cleaving 2a peptide, as taught by Wilson, between two coding sequences allows for the sequences encoding IL-10 and IL10R1 to be expressed separately.
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
(3) Claim 12-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/009955 A1, Chavez et al., published January 22, 2015, IDS and US Pat. No., 5,716,804, Moore et al., when taken with Iyer et al., Crit Rev Immunol. 2012 ; 32(1): 23–63; Author Manuscript, pages 1-43, as applied to claims 1-10, 15-19 above, and further in view of US 2009/0035256 A1 to Sommer et al., published February 5, 2009, IDS.
Chavez, Moore and Iyer are detailed and relied upon as summarized above. They do not explicitly teach that the inflammation is caused by neuropathic or chronic pain and the one or more vectors are delivered by intrathecal injection (claim 12); the inflammation is caused by MS and the one or more vectors are delivered by intrathecal injection (claim 13); the inflammation is caused by an autoimmune disease and the one or more vectors are delivered by intrathecal injection (claim 14).
However, prior to the effective date of the instant invention, Sommer further teaches treating autoimmune diseases associated with inflammation with a vector encoding IL-10 (¶6) by intrathecal injection (p. 14, ¶156-157).
Thus, regarding claim 12, Sommer teaches that intrathecal injection is a preferred mode of delivery because it keeps the expression of viral vectors local due to the rapid degradation of IL-10 and intrathecal gene therapy mimics lumbar puncture administration that is already in routine use in humans. Ibid.
Regarding claim 13, Sommer teaches their method can treat neuropathic pain by MS (claim 8; p. 1, ¶11)
Regarding claim 14, Sommer teaches that inflammation from various autoimmune diseases can be treated intrathecally (p. 6-4, ¶86-87)
Accordingly, it would have been obvious to the skilled artisan to modify the teachings of Chavez, Moore and Iyer, and administer the vectors by intrathecal injection to treat inflammation caused by disease such as MS or autoimmune diseases, as taught by Sommer, with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to deliver the vectors intrathecally because Sommer teaches that intrathecal injection is a preferred mode of delivery because it keeps the expression of viral vectors local due to the rapid degradation of IL-10 and intrathecal gene therapy mimics lumbar puncture administration that is already in routine use in humans. See p. 14, ¶156-157.
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
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 1-19 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 the following:
An ex vivo cell therapy method of treating neuroinflammation or suppressing inflammation in the CNS of a subject in need thereof, comprising administering an antigen-presenting cell to the CNS of said subject, wherein the antigen-presenting cells comprises a first nucleic acid encoding an IL-10 and a second nucleic acid encoding an IL-10R1, both nucleic acids operably liked to a constitutive promoter, wherein the antigen-presenting cell co-expresses of the IL-10 and IL10R1 in the CSF of the subject wherein neuroinflammation or inflammation in the CNS is suppressed; and
An in vivo gene therapy method for treating neuroinflammation or suppressing inflammation in the CNS of a subjection comprising intrathecally administering an AAV9 vector comprising a first nucleic acid encoding an IL-10 and a second nucleic acid encoding an IL-10R1, both nucleic acids operably liked to a constitutive promoter to said subject, wherein the AAV9 vector transduces antigen presenting cells in the CSF and the antigen-presenting cells co-expresses of the IL-10 and IL10R1 in the CSF of the subject, wherein neuroinflammation or inflammation of the CNS is suppressed.
The specification does not reasonably provide enablement for the following: (1) antigen presenting cells expressing IL-10 and IL10R1 in the CSF and treating inflammation anywhere in the body other than inflammation in the CNS; (2) any route of administration; and (3) any expression vector for the in vitro gene therapy embodiments.
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 use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: The amended claims are directed to a method treating inflammation in a subject that result in expression of IL-10 and IL10R1 from APC from an expression vector in the subject, wherein the IL-10 is expressed at a concentration of greater than about 0.5 ng/mL in the CSF and IL10 signaling downregulation is overcome.
Breadth of the Claims: The amendments to the claims specify, “wherein the IL10 peptide is expressed at a concentration in the cerebrospinal fluid of greater than about 0.5 ng/mL”. The claims continue to recite that this is “A method for treating inflammation in a subject”. The claims do not specify the type of inflammation or where the inflammation is present in the body of the subject. As such, the breadth of the amended claims encompasses treating any inflammation any wherein the body of the subject by expressing the IL10-peptide in the CSF. The method step is broadly recited as “expressing from one or more bacterial, viral phage, cosmid, or artificial chromosomal vectors” IL10 and IL101R in antigen presenting cells. Thus the breadth of this active method step encompasses two distinct methods, a cell therapy method and a gene therapy method. An ex vivo cell therapy, wherein the antigen-presenting cells are transduced with one or more of the claimed vector that must comprise some form of an exogenous nucleic acid encoding the IL10 and the IL10R1 protein and administering the transduced antigen-presenting cells to the subject by any route of administration to arrive at antigen-presenting cells that express and secrete IL10 into the CSF, thereby treating inflammation anywhere in the subject or systemically. The in vivo gene therapy method comprises administering any of the claimed vectors to the subject by any route of administration to arrive at antigen-presenting cells transfected and expressing a specific amount of IL-10 (0.5 ng/mL) in the CSF of the subject thereby treating inflammation anywhere in the subject or systemically.
Specific Guidance/Working Examples: The specification provides the following guidance (citations are from the pregrant publication):
[0045] It has been found that significant suppression of a large spectrum of inflammatory mediators can be achieved through the actions of the anti-inflammatory cytokine interleukin 10 (IL-10). IL-10 is a natural product of both astrocytes and microglia, and binds to receptors expressed by these cells producing autocrine regulation of localized inflammatory responses produced by these cells. Because of the complexity of inflammation, any agent with the capacity to re-establish normal microglial function must be able to target many different sub-systems simultaneously. IL-10 forms a tripartite complex with two receptors: IL-10R1 and IL-10R2; binding primarily to IL-10R1 (Ding et al., J. Immunol., 167(12):6884-92 (2001)) where this complex then engages IL-10R2. IL-10R2 is a more abundant and promiscuous signaling subunit than IL-10R1 that also complexes with IL-22 and its primary receptor (Kotenko et al., J. Biol. Chem., 276(4):2725-32 (2001)). IL-10R1 is present at low levels in the cell membrane of antigen-presenting cells and is upregulated by IL-10 signaling and by inflammatory mediators like LPS (Ledeboer et al., Eur. J. Neurosci., 16(7):1175-85 (2002)). The upregulation enhances signaling through the IL-10R2 receptor activating downstream effector molecules, such as JAK1, TYK2 and STAT 1 and STAT 3, and enhances signaling indirectly through PI3K-AKT. This coordinated signaling is responsible for the anti-inflammatory effect of IL-10 as well as its ability to stimulate IgG production and B-cell proliferation, even as it down-regulates antigen presentation on antigen-presenting cells, such as macrophages and T-cells. When IL-10 over-stimulates target cells, two members of a class of eight proteins called Suppressor of Cytokine Signaling (SOCS) are induced (Ding et al., J. Immunol., 170(3):1383-91 (2003), Kazi et al., Cell Mol. Life Sci., 71(17):3297-3310 (2014)). SOCS1 and SOCS3 are induced by IL-10 in a concentration-dependent manner, but SOCS1 specifically inhibits IL-10 signaling (Ding et al. 2003, supra) and IL-10R1 is ubiquitinated by SOCS3, an E3 ubiquitin ligase, thereby down-regulating membrane-bound IL-10R1 by proteasomal targeting (Wei et al., J. Interferon Cytokine Res., 26(5):281-90 (2006)). The present inventors have found that, at concentrations that exceed about 0.5 ng/mL, IL-10 paradoxically inhibits its own activity. Without being bound by any one theory, this inhibition may explain why virally-mediated IL-10 expression, although constitutive, has an early therapeutic effect on neuropathic pain that wears off relatively quickly, whereas intrathecal plasmid IL-10 provides up to 12 weeks of effect. That is, it is this phenomenon that explains why very high levels of adenovirus-driven cerebrospinal fluid IL-10 concentrations (˜10 ng/mL) result in a lack of therapeutic effect on pain in contrast to the greater effect on pain from much lower concentrations of cerebrospinal fluid IL-10 (˜150 pg/mL) seen after IL-10 plasmid injection. The present invention thus provides a second generation therapy that dramatically widens the therapeutic window of IL-10 by co-expressing IL-10 with its primary receptor IL-10R1 to achieve constitutive autocrine signaling on antigen-presenting (IL-10R2-positive) cells.
[0046] The invention generally provides methods and therapeutic anti-inflammatory compositions for treating inflammatory diseases and conditions, as well as the symptoms and physiological damage associated with inflammatory diseases. The invention also provides for using the methods and therapeutic anti-inflammatory compositions of the invention in research of inflammatory diseases, including identifying pharmaceuticals, small molecules and/or biologics that may be used in conjunction in a “cocktail” with the therapeutic compositions of the present invention. The methods comprise the step of administering to a subject an IL-10/IL-10R1 expression vector comprising an IL-10 coding sequence and an IL-10R1 coding sequence. The IL-10/IL-10R1 expression vectors of the present invention are generally suspended in a diluent to form a therapeutic composition. The anti-inflammatory therapeutic compositions may consist of a single “naked” bacterial vector or viral vector capable of expressing both of the IL-10 and IL-10R1 coding sequences and transforming or transducing antigen-presenting cells in a subject, two bacterial or viral vectors where one vector encodes the IL-10 peptide and the vector encodes the IL-10R1 peptide, encapsulated vectors, or transduced antigen-presenting cells expressing IL-10 and IL-10R1.
[0065] Where delivery of the IL-10/IL-10R1 expression vector directly to a subject via intrathecal or intra-articular injection is contemplated, the IL-10/Il-10R1 expression vector preferably is viral-based as described supra. However, in embodiments where transformed or transduced antigen-presenting cells are administered to a subject as described in more detail infra, it is also contemplated that antigen-presenting cells of choice can be engineered to produce human artificial chromosomes that express the IL-10 and IL-10R1 peptides.
[0067] The IL-10/IL-10R1 expression vectors can be introduced into a subject either in vivo or in vitro (also termed ex vivo). In vivo introduction comprises administering the IL-10/IL-10R1 expression vectors directly to a subject, and in-vitro introduction comprises administering antigen-presenting cells that have been engineered to co-express IL-10 and IL-10R1 to a subject.
[0069] Alternatively, if transduced in vitro, the desired antigen-presenting recipient cells are preferably removed from a subject, transformed or transduced with the IL-10/IL-10R1 expression vector and reintroduced into the subject (that is, the antigen-presenting cells are autologous). Alternatively, however, syngeneic or xenogeneic antigen-presenting cells (such as from an established antigen-presenting cell line that has been stably transformed with the IL-10/IL-10R1 expression vector) can be transformed or transduced for delivery in the subject. Antigen-presenting cells or precursors thereof that may be transformed or transduced include any cells from the monocyte family, including monoblasts, monocytes, astrocytes, oligodendrocytes, microglia, macrophages, B cells, dendritic cells foam cells, lymphoblasts, and B lymphocytes. Precursor antigen-presenting cells may be transduced and cultured in the undifferentiated state, then differentiated in vitro before delivery to the subject.
[0070] The IL-10/IL-10R1 expression vector can be delivered to the antigen-presenting cells to be engineered by any method known in the art. The terms transfection and transformation refer to the taking up of exogenous nucleic acid, e.g., an expression vector, by a host cell whether or not any coding sequences are, in fact, expressed. Numerous methods of transfection are known to the ordinarily skilled artisan, for example, by Agrobacterium-mediated transformation, protoplast transformation (including polyethylene glycol (PEG)-mediated transformation, electroporation, protoplast fusion, and microcell fusion), lipid-mediated delivery, liposomes, electroporation, sonoporation, microinjection, particle bombardment and silicon carbide whisker-mediated transformation and combinations thereof; direct uptake using calcium phosphate; polyethylene glycol (PEG)-mediated DNA uptake; lipofection; microcell fusion; lipid-mediated carrier systems; or other suitable methods. Successful transfection is generally recognized by detection of the presence of IL-10/IL-10R1 gene transcripts or IL-10/IL-10R1 peptides within the transfected cell.
[0071] Because viral vectors are a preferred embodiment of the invention, antigen-presenting cells are preferably transduced using the viral vector. The use of viral infection is unique in that a virus' naturally occurring means of introducing its genetic material into a cell is taken advantage of to transfer a nucleic acid molecule of interest into a cell. As discussed supra, examples of viruses modified and applied to such techniques include adenoviruses, adeno-associated viruses, and retroviruses. Generally, nucleic acid molecules of interest may be cloned into a viral genome. Upon replication and packaging of the viral genome, the resultant viral particle is capable of delivering the nucleic acid of interest into a cell via the viral entry mechanism. Commonly, the viral genome is first made replication deficient by nucleic acid manipulation before Lite addition of the nucleic acid of interest. The resultant viral genome, or viral vector, requires the use of a helper virus or a packaging system to complete viral particle assembly and release from a cell.
Example 2—Supporting Data
[0089] It should be noted that IL-10 displays some idiosyncrasies in terms of species-specificity. For example, mouse IL-10 does not interact with the human IL-10 receptor, although human IL-10 does bind to the mouse IL-10 receptor, and human IL-10 binds weakly with the rat IL-10 receptor. For this reason, rat IL-10 (rIL-10) has generally been used in rat experiments, and human IL-10 (hIL-10) has been used in mouse, dog and horse studies. The fact that hIL-10 activates the rat IL-10 receptor only at high concentrations is a very useful feature, because co-expression of human IL-10R1 in target rat tissues results in full response to human IL-10. In order to simplify delivery, adeno-associated viruses (AAV) encoding rIL-10, hIL-10, or hIL-10R1 were constructed. Serotype 9 was chosen because AAV9 distributes very well when injected intrathecally and transduces a wide variety of cells including antigen-presenting cells such as astrocytes that themselves express IL-10R1. As shown in FIG. 1, AAV9-hIL-10 is anti-allodynic in the rat Chronic Constriction Injury (CCI) model of neuropathic pain, but the effect wears off. However, a 1:1 mixture of AAV9-hIL-10 and AAV9-hIL10R1 directs stable elimination of allodynia in this model (FIG. 2), consistent with the hypothesis that combined IL-10 and IL-10R1 expression permits much higher intrathecal dosing to drive widespread suppression of inflammation throughout the spinal cord and white matter tracts. Open circles=AAV9-hIL-10R1; closed circles=AAV9-hIL-10+XR-101; closed squares=AAV9-hIL-10Ra+AAV9-hIL-10.
While the claims are broadly directed to a cell therapy or gene therapy method that administers by any route of administration either antigen-presenting cells transfected with a vector and expressing IL10 and IL10R1 or the claimed vectors encoding IL10 and IL10R1, the specification and working examples more narrowly provide guidance to a direct type of administration to the CSF and CNS. Further in terms of the gene therapy, the specification describes the use of an AAV9 vector known for its ability to specifically transduce antigen-presenting cells and other cells of the CNS and direct delivery to the CNS and CSF via intrathecal administration. The specification does not provide any guidance to a means of indirect delivery of the cell or gene therapy to specifically transduce antigen presenting cells of the CSF in a manner that would specifically result in expression of a highly specific concentration of IL10 in the CSF as claimed. Further [0045] of the specification teaches the use of different vectors (i.e. plasmid versus adenoviral vector) result in different expression levels and thus different concentrations of IL10. Therefore, the specification suggest that vector and administration impact expression in an unpredictable manner. Thus, the specification fails to provide predictable guidance for the breadth of the instant claims.
State of the Art: The post-filing art of Mapunda et al. (Frontiers in Immunology. Feb 2022. Vol 12. Article 805657. Pp. 1-15), report, “Understanding how and where immune cells are primed, how they access the CNS in MS and how immunomodulatory treatments affect neuroinflammation requires a proper knowledge on the mechanisms regulating immune cell trafficking and the special anatomy of the CNS. The brain barriers divide the CNS into different compartments that differ with respect to their accessibility to cells of the innate and adaptive immune system. In steady state, the blood-brain barrier (BBB) limits immune cell trafficking to activated T cells, which can reach the cerebrospinal fluid (CSF) filled compartments to ensure CNS immune surveillance. In MS immune cells breach a second barrier, the glia limitans to reach the CNS parenchyma.” Page 1, paragraph 1.
As such, the state of the art teaches that antigen-presenting cells and many gene therapy vectors will not predictably arrive in the CSF and CNS, the intended site of therapy because of innate protective barrier in both the CSF and CNS. The specification solely provides specific guidance to direct administration of antigen presenting cells or gene therapy vectors. As such, the state of the art does not supplement the shortcomings of the specification and further teach unpredictability in the make and use of the claimed invention.
In conclusion, the breadth of the claims to a method of treating inflammation in any particle of the body by co-expressing 10IL and IL10R1 in the CSF lacks enablement because the specification fail to provide specific, predictable guidance to treating any other inflammation other than inflammation of the CNS via direct administration in to the CSF. Further, the prior art teaches that blood brain barrier and other known protective barriers will not predictably allow for the passage of antigen-presenting cells or gene therapy vector and thus would not predictably arrive at the CSF as the claims require.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
Prosecution Insights