565848
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 11, 2026, has been entered.
DETAILED ACTION
Applicant’s response filed June 26, 2025, has been considered. Rejections and/or objections not reiterated from the previous office action mailed March 26, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant has elected group I, drawn to a genetically modified dendritic cell or precursor cell thereof modified with a nucleic acid construct and the construct (claims 1-11, 18-19, and 31-36).
Election of Applicant’s invention(s) was made without traverse in the reply filed
on November 17, 2023.
The claims, filed on February 11, 2026, are acknowledged. Claims 8, 10, 12, 17, and 33-38 were cancelled. Claims 13-16 and 20-30 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Claims 1-7, 9, 11, and 18-19, 31-32, and 39-40 are pending.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Silvia Gregori on February 11, 2026, has been considered but is insufficient to overcome the rejections of instant claims based upon 35 U.S.C 103 as set forth in the current Office action for the following reasons:
First, the Gregori declaration argues that the obviousness allegation is based on an oversimplification of the prior art. Generating tolerogenic DCs suitable for promoting tolerance via induction of antigen-specific Tr1 cells requires the simultaneous realisation of three interdependent elements: (i) antigen expression, (ii) IL-10-driven tolerogenic programming, and (iii) coordinated expression from a bidirectional LV. None of the cited references teaches or suggests all three elements together, and there is no reasonable expectation of success in achieving tolerogenic dendritic cells using this combination.
Regarding the substitution of IRF3 2D in Escors for IL-10, this is allegedly taught in Rea and Henry is an oversimplification of the underlying biology of dendritic cell and IRF3 signalling. Escors discloses IRF3 activation in murine and human DCs, an indirect effect of this being the production of IL-10 (Figure 4A, page 3055), which is nonetheless at levels lower than the levels produced by the cells of the present invention (present application Figure 16A). Escors does not teach that IRF3 activation is mechanistically equivalent to IL-10, nor does it suggest that IRF3 2D can be substituted for IL-10 and achieve the same tolerogenic outcome. As documented in the scientific literature, IRF3 is a pleiotropic transcription factor that controls hundreds of antiviral and immunogenic genes, whereas IL-10 is a terminal effector cytokine that acts via STAT3-dependent tolerogenic circuits. The pathways are distinct, non-linear, and context dependent. The fact that Escors observed IL-10 production downstream of IRF3 activation simply does not provide a reasonable expectation that direct IL-10 expression alone would function equivalently to IRF3 activation in human dendritic cells, particularly in the specific context of antigen presentation (page 2, paragraph 3-page 3, paragraph 1).
Applicant's arguments in the declaration have been fully considered but they are not persuasive.
Regarding Applicant’s arguments against the substitution of IRF-3 for IL-10, Escors teaches that they have shown that 2 distinct signaling pathways in DCs lead to antigen-specific suppression, one of which is IRF3 activation causes IL-10 secretion. Additionally, Rea and Henry show that a transgene encoding IL-10 is sufficient to increase IL-10 secretion and produce a state of antigen-specific immune suppression. Additionally, Henry teaches that the transducing dendritic cells with IL-10 also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw with the IRF3 transgene. Furthermore, the inventions disclosed in Escors and Rea both relate to inducing tolerance of dendritic cells to manage autoimmunity and Escors and Henry teach that their dendritic cells induce tolerance to allergens. Escors teaches that IRF3 requires MYD88 to secrete IL-10 and loss of the β1 chain of the type I IFN receptor reduced IL-10 secretion. Rea and Henry teach that vectors (adenovirus and lentivirus, respectively) encoding IL-10 increase IL-10 expression significantly in human and mouse dendritic cells. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Escors already created a dual lentiviral vector to transduce human dendritic cells and Besche teaches that IL-10 secretion from dendritic cells can be increased using a dual lentiviral vector encoding IL-10 under the control of a CMV promoter. Furthermore, Escors acknowledges that the promoter was switched to a CMV promoter to allow expression in human dendritic cells with a different combination of activator and antigen.
Based on the combined teachings of Escors, Rea, and Henry, one of ordinary skill in the art would understand that although IRF-3 may have pleiotropic effects, increased expression of IL-10 alone is sufficient to cause a tolerogenic immune phenotype, produce a state of antigen-specific immune suppression, and increase the numbers of CD4+CD25+Foxp3+ regulatory T cells. Therefore, it would have been obvious to substitute the IRF-3 gene for IL-10 as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3, and the IL-10 transgene has been shown to reproduce many of the same phenotypic changes identified Escors.
Additionally, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the specific levels of IL-10 produced by the cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Second, the Gregori declaration argues that it is alleged that Rea and Henry show induction of tolerogenic phenotypes in immature dendritic cells through Ad- or LV-mediated IL-10 expression. Insofar as this is used to support the obviousness of exchanging the IRF3 2D of Escors for direct IL-10 expression, this is also an over-simplification. Human dendritic cells are highly sensitive to transgene context and viral sensing. Additionally, Rea explicitly notes species-specific differences in IL-10 responses. Neither Rea or Henry provide guidance or predictability for generating human dendritic cells that stably co-express a tolerogenic cytokine and a specific antigen, thereby inducing Tr1 cells (page 3, paragraph 2).
Applicant's arguments in the declaration have been fully considered but they are not persuasive.
As an initial matter, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues human dendritic cells are highly sensitive to transgene context and viral sensing, they have not provided any evidence that this is the case.
Furthermore, 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 rejection is based on the combined teachings of Escors, Rea, Henry, and Besche which as stated in the rejection above, teach all of the elements of the rejected claims.
1. Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10.
2. Rea teaches dendritic cells can be modified to express the exogenous transgene IL-10.
3. Henry provides the motivation to make and use dendritic cells expressing IL-10.
4. Besche teaches that IL-10 can be expressed in a dual transgene lentiviral vector
Therefore, one of ordinary skill in the art could have pursued the known potential option of substituting the IL-10 transgene with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the reference of Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10, (2) the reference of Rea et al. contained a detailed enabling methodology for expressing IL-10 that could have been easily applied to the dendritic cells of Escors, (2) Henry provides a suggestion to apply the substitution to the dendritic cells of Escors to improve their immunoregulatory functions, thereby suggesting modification of the cells of Escors to include other transgenes to increase IL-10 would be successful.
Furthermore, Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a genetically modified dendritic cell. Furthermore, the Federal Circuit found that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
It is worth noting that although there are differences in between the references, they all relate to expressing transgenes associated with IL-10 secretion in dendritic cells to regulate dendritic cell immune activity. As such, one of ordinary skill in the art would consider these compatible references. Furthermore, one of ordinary skill in the art would have a reasonable expectation of success in generating claimed compositions based on the combined teachings of Escors, Rea, and Henry. Escors successfully reduces to practice a genetically modified dendritic cell modified by lentiviruses comprising a nucleic acid encoding a human invariant chain (a MHC class II invariant chain) fused to OVA MHC class I and class II epitopes and an IRF3 activator (a transgene that causes IL-10 secretion). Rea successfully reduces to practice that human IL-10 can be expressed from a viral vector and administered to dendritic cells to significantly increase IL-10 secretion of the dendritic cell. Henry successfully reduces to practice that lentiviral vectors (the same vector of Escors) encoding IL-10 can transduce dendritic cells and also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw increase with the IRF3 transgene. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Therefore, it would have been obvious to one of ordinary skill in the art that the teachings of Escors, Rea, and Henry could be combined to teach the claimed compositions.
Third, the Gregori declaration argues that regarding the bidirectional promoter, Squadrito discloses bidirectional LVs co-expressing a transgene and GFP. Contrary to the Office Action's assertion, this teaching does not make modification of the nucleic acid construct allegedly arrived at from the combination of Escors, Rea and Henry trivial. Bidirectional promoter systems are technically challenging due to risks including transcriptional competition, silencing, and imbalanced expression between the two transgenes. These issues are exacerbated in primary dendritic cells, which possess antiviral sensing machinery and epigenetic mechanisms that can unpredictably alter transgene expression. Simply applying Squadrito' s architecture to Escors type lentiviral vectors would not have assured stable, coordinated expression of both the antigen and IL-10 transgenes required for the tolerogenic phenotype of the claimed cells. There is no teaching or suggestion in Squadrito regarding tolerogenic programming or induction of antigen-specific Tregs (page 3, paragraph 3).
Applicant's arguments in the declaration have been fully considered but they are not persuasive.
As an initial matter, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues bidirectional promoter systems are technically challenging due to risks including transcriptional competition, silencing, and imbalanced expression between the two transgenes and these issues are exacerbated in primary dendritic cells, which possess antiviral sensing machinery and epigenetic mechanisms that can unpredictably alter transgene expression, they have not provided any evidence that this is the case.
Furthermore, 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 rejection is based on the combined teachings of Escors, Rea, Henry, Besche, and Squadrito which as stated in the rejection above, teach all of the elements of the rejected claims.
1. Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10.
2. Rea teaches dendritic cells can be modified to express the exogenous transgene IL-10.
3. Henry provides the motivation to make and use dendritic cells expressing IL-10
4. Besche teaches that IL-10 can be expressed in a dual transgene lentiviral vector
5. Squadrito successfully reduces to practice that bidirectional vectors with an SSFV promoter of a therapeutic transgene and a CMV promoter driving expression of GFP can transduce dendritic cells
Therefore, one of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Escors and Squadrito use the same promoters (SFFV and CMV) in the lentivirus and transduce the same cell type (dendritic cells) and Squadrito has successfully reduced to practice that bidirectional lentiviruses can express both transgenes in dendritic cells. As such, it would have been obvious that one could change the monodirectional construct of Escors into a bidirectional construct in the vein of Squadrito. Furthermore, there are only two options for the arrangement of promoter as either monodirectional or bidirectional, and one of ordinary skill would have immediately envisioned the bidirectional option from such a small genus. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Furthermore, Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a genetically modified dendritic cell. Furthermore, the Federal Circuit found that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 6, 11, 18-19, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010). This is a new rejection substantially similar to a previous rejection of record. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claims 1 and 18, Escors teaches a genetically modified dendritic cell modified by lentiviruses comprising a nucleic acid encoding a human invariant chain (a MHC class II invariant chain) fused to OVA MHC class I and class II epitopes and an IRF3 activator. Lentivectors were administered to mice by subcutaneous vaccination because dermal DCs are targeted through this immunization route. Escors teaches that IRF3 suppressed the immune response by upregulating the number of CD4+CD25+Foxp3+ dendritic cells (page 3055, column 2, paragraph 3-page 3057, column 1, paragraph 2 and Figure 5). Escors teaches that dendritic cells transduced with a lentivirus encoding the IRF3 activator causes IL-10 secretion and this IL-10 secretion is impaired in MYD88-deficient dendritic cells and in mice deficient for the β1 chain of the type I IFN receptor (Figure 4 and page 3055, column 1, paragraph 1-column 2, paragraph 1). Escors teaches that they have shown that 2 distinct signaling pathways in DCs lead to antigen-specific suppression, one of which is IRF3 activation causes IL-10 secretion. Escors teaches that tolerance to pathogenic auto-antigens or allergens could be induced by injection of DCs expressing IRF3 or coexpression of transgenes with modulators of DC maturation such as activators of IRF3 could suppress immune responses against the transgene (page 3059, column 1, paragraph 1- column 2, paragraph 1). Escors also teaches that they transduced human dendritic cells with a similar lentiviral construct encoding the activator MKK6EE and the antigen MELAN-A. The ubiquitin promoter was not active in huDCs, so this promoter was substituted by CMV promoter (page 3057, column 2, paragraph 3 and Figure 7).
Although Escors highlights the role of IRF3 activation in causing IL-10 secretion and antigen-specific suppression, Escors does not teach wherein the nucleic acid construct comprises a nucleic acid encoding human IL-10.
However, Rea teaches that immature human dendritic cells were infected with recombinant adenoviruses encoding human IL-10 resulting in the secretion of large amounts of IL-10. Rea teaches that human DCs genetically engineered to produce IL-10 may be exploited for the modulation of harmful Th1-type responses in transplantation and autoimmune diseases. Rea teaches that in vivo administration of rAdIL-10 DC may be employed for instalment of a prolonged state of antigen-specific immune suppression (page 1354, column 2, paragraph 1, abstract, and Figure 1). Furthermore, Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction. Rea teaches that rAdIL-10 may be useful in inducing immunologic tolerance (page 1353, column 1, paragraph 2).
Henry teaches that OVA is used to model asthma and that dendritic cells transduced to express IL-10 helped protect from airway allergy by increasing the number of Ag-specific CD4+CD25+Foxp3+ regulatory T cells (abstract, page 7231, column 1, paragraphs 9-column 2. Paragraph 1, and page 7236, column 1, paragraph paragraph 3-column 2, paragraph 3). Henry teaches that mouse bone marrow derived dendritic cells were infected with recombinant lentiviruses encoding murine IL-10 resulting in the secretion of large amounts of IL-10 (Figure 1 and page 7231, column 1, paragraphs 4-7).
Besche teaches that dendritic cells can be transduced with lentiviral vectors encoding IL-10 under the control of a first promoter and encoding a second transgene (GFP) under the control of a second promoter and result in increased IL-10 secretion in dendritic cells (Figure 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the IRF3 gene in the lentivirus encoding IRF3 and IiOVA used to make genetically modified dendritic cells of Escors with a nucleic acid sequence encoding the human IL-10, as identified by Rea, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the substitution with a reasonable expectation of success because the inventions disclosed in Escors and Rea both relate to inducing tolerance of dendritic cells to manage autoimmunity and Escors and Henry teach that their dendritic cells induce tolerance to allergens. Escors teaches that IRF3 requires MYD88 to secrete IL-10 and loss of the β1 chain of the type I IFN receptor reduced IL-10 secretion. Rea and Henry teach that vectors (adenovirus and lentivirus, respectively) encoding IL-10 increase IL-10 expression significantly in human and mouse dendritic cells. Rea (300,000 pg/mL (Figure 1)) and Henry (25,000 pg/mL (Figure 1)) teach that vectors (adenovirus and lentivirus, respectively) encoding IL-10 increase IL-10 expression significantly in human and mouse dendritic cells (and significantly more than what is found when using the IFR3 2D mutant of Escors (50 pg/mL (Figure 4)). Additionally, Henry teaches that the transducing dendritic cells with IL-10 also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw with the IRF3 transgene. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Additionally, Rea and Henry show that a transgene encoding IL-10 is sufficient to increase IL-10 secretion and produce a state of antigen-specific immune suppression. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Escors already created a dual lentiviral vector to transduce human dendritic cells and Besche teaches that IL-10 secretion from dendritic cells can be increased using a dual lentiviral vector encoding IL-10 under the control of a CMV promoter. Furthermore, Escors acknowledges that the promoter was switched to a CMV promoter to allow expression in human dendritic cells with a different combination of activator and antigen. As such, it would have been obvious that one could transduce human dendritic cells with a lentivirus encoding IiOva and IL-10 transgenes to produce the instant invention of claims 1 and 18. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 3, Escors teaches that the first promoter is SFFV and the second promoter is CMV in human cells (Figures 5 and 7 and page 3057, column 2, paragraph 3).
Regarding claim 6, OVA (ovalbumin) is a known allergen.
Regarding claims 11 and 19, Escors teaches that the nucleic acid construct is inserted into a lentiviral vector (Figures 5 and 7).
Regarding claim 31, Henry teaches that they transduced dendritic cells in vitro before administering them to asthma model mice. The transduced dendritic cells were isolated in fresh culture medium before administration (a pharmaceutically acceptable carrier) (page 7231, column 1, paragraph 2-column 2, paragraph 2). It would have been obvious to transduce the cells ex vivo before administering them in a pharmaceutically acceptable carrier (e.g. culture media). First, it would ensure the lentivirus only infects dendritic cells as in vivo administration of the lentivirus would infect other cell types, limiting the number of transduced dendritic cells. Second, ex vivo transduction would allow for assessing the cells to ensure they express and/or secrete IL-10 and the antigen prior to administration to the patient, increasing the likelihood of success. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed February 11, 2026, are acknowledged.
First, Applicant argues that the IFR3 2D mutant induced IL-10 expression in transduced dendritic cells (DCs) which lead to systemic Treg expansion. Therefore, a person of ordinary skill in the art would consider the IRF3 2D mutant to be a successful approach to generating immunosuppressive DCs and would not look to directly express IL-10 as a transgene. Applicant argues that the assertion that one of ordinary skill in the art would consider Rea is based on hindsight as Escors considers the IRF3 2D expression to be advantageous and there would, therefore, be no motivation to consider alternative methods of IL-10 production (page 10, paragraph 1-page 11, paragraph 3).
Applicant's arguments have been fully considered but they are not persuasive.
First, Applicant argues that the obviousness allegation is based on an oversimplification of the prior art. Escors discloses a constitutively active IRF3, and notes that, inter alia, this results in IL-10 expression. However, as Dr Gregori explains, IRF3 is a pleiotropic transcription factor that controls hundreds of antiviral and immunogenic genes. For example, Escors notes that constitutively active IRF3 also results in IFN-β expression. IRF3 activation can and would be expected to affect many signalling pathways. Indeed, Dr. Gregori describes that IL-10 is a terminal effector cytokine that acts via STAT3-dependent tolerogenic circuits. These pathways are distinct, non-linear and context dependent (Point 7, Gregori declaration). The person of ordinary skill in the relevant art would understand the complex signalling mechanisms that are present in the cells and in the mechanistic processes that are relevant to the present invention. The office action effectively reduces the results observed in Escors from constitutive IRF3 activation to equate to the effect of IL-10 expression only. This is simply not the case. The effect of constitutive IRF3 activation on tolerogenicity and immune signalling of a dendritic cell cannot be deemed to be solely attributable to IL-10 expression from the teaching of Escors (page 10, paragraph 2-page 11, paragraph 3).
Applicant's arguments have been fully considered but they are not persuasive.
Regarding Applicant’s arguments against the substitution of IRF-3 for IL-10, Escors teaches that they have shown that 2 distinct signaling pathways in DCs lead to antigen-specific suppression, one of which is IRF3 activation causes IL-10 secretion. Additionally, Rea and Henry show that a transgene encoding IL-10 is sufficient to increase IL-10 secretion and produce a state of antigen-specific immune suppression. Additionally, Henry teaches that the transducing dendritic cells with IL-10 also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw with the IRF3 transgene. Furthermore, the inventions disclosed in Escors and Rea both relate to inducing tolerance of dendritic cells to manage autoimmunity and Escors and Henry teach that their dendritic cells induce tolerance to allergens. Escors teaches that IRF3 requires MYD88 to secrete IL-10 and loss of the β1 chain of the type I IFN receptor reduced IL-10 secretion. Rea and Henry teach that vectors (adenovirus and lentivirus, respectively) encoding IL-10 increase IL-10 expression significantly in human and mouse dendritic cells. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Escors already created a dual lentiviral vector to transduce human dendritic cells and Besche teaches that IL-10 secretion from dendritic cells can be increased using a dual lentiviral vector encoding IL-10 under the control of a CMV promoter. Furthermore, Escors acknowledges that the promoter was switched to a CMV promoter to allow expression in human dendritic cells with a different combination of activator and antigen.
Based on the combined teachings of Escors, Rea, and Henry, one of ordinary skill in the art would understand that although IRF-3 may have pleiotropic effects, increased expression of IL-10 alone is sufficient to cause a tolerogenic immune phenotype, produce a state of antigen-specific immune suppression, and increase the numbers of CD4+CD25+Foxp3+ regulatory T cells. Therefore, it would have been obvious to substitute the IRF-3 gene for IL-10 as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3, and the IL-10 transgene has been shown to reproduce many of the same phenotypic changes identified Escors.
Second, Applicant argues that they previously pointed out that, having identified a method of inducing tolerance in human dendritic cells through the use of constitutive IRF3 activation, the person of ordinary skill in the art would be disincentivised to exchange IRF3 2D expression for IL-10 expression alone. The office action has alleged that Escors suggests a potential benefit to the use of IL-10 as the trans gene as it does not require co-molecules (such as MYD88 or the beta chain of the type I IFN receptor, page 9, 2nd para of the office action). However, it cannot be the case that a document that teaches a successful method of achieving a result (which is different from the approach of the present invention) actually preferentially teaches a different method that it does not test and does not disclose as achieving the desired technical result (page 11, paragraphs 4-6).
The rejection is based on the combined teachings of Escors, Rea, Henry, and Besche. Although Escors does not teach or suggest using a lentiviral vector encoding IL-10 instead of IRF-3, Escors, as stated in the rejection above, highlights that IRF3 requires MYD88 to secrete IL-10 and loss of the β1 chain of the type I IFN receptor reduced IL-10 secretion. Direct expression of IL-10 as the transgene would not have this disadvantage. Therefore, Escors teaches a potential benefit to using IL-10 as the transgene over IRF3 2D mutants. Furthermore, as identified in the rejection and arguments above, direct expression of the IL-10 transgene has been shown to reproduce many of the same phenotypic changes identified Escors
As such, based on the combined teachings of Escors, Rea, Henry, and Besche, it would have been obvious to consider alternative methods of IL-10 production to get around the requirement for co-molecules for IL-10 secretion of IRF3, and it would have been obvious to use an IL-10 transgene as Rea and Henry successfully reduce to practice that high levels of IL-10 secretion can be accomplished through an IL-10 transgene.
Third, Applicant argues that Dr Gregori explains that human dendritic cells are highly sensitive to transgene context and viral sensing (Point 8, Gregori declaration). The methods of Rea and Henry differ from that of Escors in significant and meaningful ways. Rea discloses the use of adenovirus vector rather than a lentiviral vector. Henry uses murine IL-10 rather than human IL-10. As Dr Gregori describes and as Rea itself discloses, there are species-specific differences in IL-10 responses. The office action alleges this would motivate the change from murine to human IL-10. On the contrary. The knowledge that species-specific effects of IL-10 are present would instead demotivate the person of ordinary skill in the art from changing the IL-10 species used in Henry. Henry demonstrates a functional method, and the skilled person would have no reasonable expectation of success in changing the IL-10 species given the presence of species-specific effects. Moreover, neither Rea nor Henry shows a tolerogenic phenotype in a dendritic cell that has been engineered to stably express both a cytokine and an antigen-fusion protein. The only reference that demonstrates such a phenotype in the context of the expression of an antigen-fusion protein is Escors, and Escors only demonstrates this through expression of constitutively active IRF3. As previously mentioned, the effects of this trans gene on dendritic cell signalling cannot be considered representative of the effect of direct IL-10 expression alone (page 11, paragraph 7-page 12, paragraph 7).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues human dendritic cells are highly sensitive to transgene context and viral sensing, they have not provided any evidence that this is the case.
Furthermore, 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 rejection is based on the combined teachings of Escors, Rea, Henry, and Besche which as stated in the rejection above, teach all of the elements of the rejected claims.
1. Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10.
2. Rea teaches dendritic cells can be modified to express the exogenous transgene IL-10.
3. Henry provides the motivation to make and use dendritic cells expressing IL-10.
4. Besche teaches that IL-10 can be expressed in a dual transgene lentiviral vector
Therefore, one of ordinary skill in the art could have pursued the known potential option of substituting the IL-10 transgene with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the reference of Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10, (2) the reference of Rea et al. contained a detailed enabling methodology for expressing IL-10 that could have been easily applied to the dendritic cells of Escors, (2) Henry provides a suggestion to apply the substitution to the dendritic cells of Escors to improve their immunoregulatory functions, thereby suggesting modification of the cells of Escors to include other transgenes to increase IL-10 would be successful.
Furthermore, Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a genetically modified dendritic cell. Furthermore, the Federal Circuit found that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
It is worth noting that although there are differences in between the references, they all relate to expressing transgenes associated with IL-10 secretion in dendritic cells to regulate dendritic cell immune activity. As such, one of ordinary skill in the art would consider these compatible references. Furthermore, one of ordinary skill in the art would have a reasonable expectation of success in generating claimed compositions based on the combined teachings of Escors, Rea, and Henry. Escors successfully reduces to practice a genetically modified dendritic cell modified by lentiviruses comprising a nucleic acid encoding a human invariant chain (a MHC class II invariant chain) fused to OVA MHC class I and class II epitopes and an IRF3 activator (a transgene that causes IL-10 secretion). Rea successfully reduces to practice that human IL-10 can be expressed from a viral vector and administered to dendritic cells to significantly increase IL-10 secretion of the dendritic cell. Henry successfully reduces to practice that lentiviral vectors (the same vector of Escors) encoding IL-10 can transduce dendritic cells and also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw increase with the IRF3 transgene. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Therefore, it would have been obvious to one of ordinary skill in the art that the teachings of Escors, Rea, and Henry could be combined to teach the claimed compositions.
Fourth, Applicant argues that the rejection is based on hindsight reasoning. The alleged disclosure of the elements is across multiple documents and requires multiple modifications that go directly against the actual direction provided in those documents to the person skilled in the art. The combinations required in the office action are arbitrary selections that ignore the actual teachings of the relevant documents - assessment of obviousness must be done from the mind of the person skilled in the art before they became aware of the present invention. The skilled person is too unimaginative to be persuaded to take the direction pointed to in the prior art. That direction is away from the present invention and it required inventive skills to take a different approach, as was done by the present inventors.
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As stated in the rejection above, Escors teaches that IRF3 requires MYD88 to secrete IL-10 and loss of the β1 chain of the type I IFN receptor reduced IL-10 secretion. On the contrary, Rea (300,000 pg/mL (Figure 1)) and Henry (25,000 pg/mL (Figure 1)) teach that vectors (adenovirus and lentivirus, respectively) encoding IL-10 increase IL-10 expression significantly in human and mouse dendritic cells (and significantly more than what is found when using the IFR3 2D mutant of Escors (50 pg/mL (Figure 4)). Additionally, Henry teaches that the transducing dendritic cells with IL-10 also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw with the IRF3 transgene. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. This provides an obvious reason to switch the transgene from IRF3 to IL-10 that was known within the art prior art (page 12, paragraph 8-page 13, paragraph 1).
MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues the combinations required in the office action are arbitrary selections that ignore the actual teachings of the relevant documents - assessment of obviousness must be done from the mind of the person skilled in the art before they became aware of the present invention and the skilled person is too unimaginative to be persuaded to take the direction pointed to in the prior art., they have not provided any evidence that this is the case.
Fifth, Applicant argues that, as stated in Dr Gregori' s declaration, the generation of the tolerogenic dendritic cells of the present invention required the simultaneous realisation of the three independent elements: (i) antigen expression, (ii) IL-10-driven tolerogenic programming, and (iii) coordinated expression from a bidirectional lentiviral vector (Point 6 of the declaration). None of the cited documents teaches or suggests all three elements together, and there is no reasonable expectation of success based only on the disparate and independent disclosures of Escors, Rea, and Henry. There is a gap in the knowledge of the person of ordinary skill in the art that is only taught by the disclosure of the present application. Firstly, there is no clear teaching that the IL-10 expression observed in Escors is a necessary or a sufficient contributor to the tolerogenic nature of the produced dendritic cells. As previously mentioned, the constitutive activation of IRF3 has effects on many effector pathways. Accordingly, as discussed above, Escors cannot provide a reasonable expectation of success in using a human IL-10 transgene only. Secondly, there are deficiencies in the teachings of Rea and Henry that would prevent the use of transgenic human IL-10 from being obvious in combination with the teaching of Escors. Escors uses a different viral vector from that of Rea, and the person of ordinary skill in the art would be uncertain as to how the switch of viral vector would affect the dendritic cell phenotype shown in Rea. Furthermore, Escors uses human IL-10, whereas Henry uses murine IL-10. The person of ordinary skill in the art would be uncertain how the switch from murine to human IL-10 would affect the dendritic cell phenotype shown in Henry. Finally, both Rea and Henry use dendritic cells that are pulsed with antigen, and do not teach an expressed antigen fusion trans gene. In the context of dendritic cells, and in respect of the specific tolerogenic phenotype that is desired, the person of ordinary skill in the art would have understood that the outcome is highly sensitive to perturbations in cell signalling that can be caused by transfection and trans gene expression (Point 8 of the declaration). From the perspective of the person of ordinary skill in the art, the expression of the antigen fusion protein in addition to IL-10 could affect the dendritic cells in ways that could not be easily predicted. Since Escors only demonstrates IRF3 activation, there could be effects of the antigen fusion protein expression that IRF3 activation compensates for, but that IL-10 expression would not (page 13, paragraph 2-page 14, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues human dendritic cells are highly sensitive to transgene context and viral sensing, they have not provided any evidence that this is the case.
Furthermore, 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 rejection is based on the combined teachings of Escors, Rea, Henry, and Besche which as stated in the rejection above, teach all of the elements of the rejected claims.
1. Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10.
2. Rea teaches dendritic cells can be modified to express the exogenous transgene IL-10.
3. Henry provides the motivation to make and use dendritic cells expressing IL-10.
4. Besche teaches that IL-10 can be expressed in a dual transgene lentiviral vector
Therefore, one of ordinary skill in the art could have pursued the known potential option of substituting the IL-10 transgene with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the reference of Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10, (2) the reference of Rea et al. contained a detailed enabling methodology for expressing IL-10 that could have been easily applied to the dendritic cells of Escors, (2) Henry provides a suggestion to apply the substitution to the dendritic cells of Escors to improve their immunoregulatory functions, thereby suggesting modification of the cells of Escors to include other transgenes to increase IL-10 would be successful.
Furthermore, Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a genetically modified dendritic cell. Furthermore, the Federal Circuit found that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
It is worth noting that although there are differences in between the references, they all relate to expressing transgenes associated with IL-10 secretion in dendritic cells to regulate dendritic cell immune activity. As such, one of ordinary skill in the art would consider these compatible references. Furthermore, one of ordinary skill in the art would have a reasonable expectation of success in generating claimed compositions based on the combined teachings of Escors, Rea, and Henry. Escors successfully reduces to practice a genetically modified dendritic cell modified by lentiviruses comprising a nucleic acid encoding a human invariant chain (a MHC class II invariant chain) fused to OVA MHC class I and class II epitopes and an IRF3 activator (a transgene that causes IL-10 secretion). Rea successfully reduces to practice that human IL-10 can be expressed from a viral vector and administered to dendritic cells to significantly increase IL-10 secretion of the dendritic cell. Henry successfully reduces to practice that lentiviral vectors (the same vector of Escors) encoding IL-10 can transduce dendritic cells and also caused the numbers of CD4+CD25+Foxp3+ regulatory T cells to increase, the same population Escors saw increase with the IRF3 transgene. As such, it would have been obvious to switch out IRF3 with IL-10 to ensure IL-10 secretion occurs as there would be no co-molecules required for IL-10 secretion if IL-10 is the transgene, unlike with IRF3. Furthermore, as Rea teaches that there are distinct differences in how human and murine dendritic cells respond to rAdIL-10 transduction, it would have been obvious to use human IL-10, as done by Rea, to transduce human dendritic cells for direct translation to human clinical settings. Therefore, it would have been obvious to one of ordinary skill in the art that the teachings of Escors, Rea, and Henry could be combined to teach the claimed compositions.
Claims 1, 2, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claim 1 above, and further in view of World Intellectual Property Organization Patent Application No. 2018187590 (Brito, April 2018 filing date). This is a new rejection substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
The teachings of Escors, Rea, Henry, and Besche are as discussed above
The combined teachings of Escors, Rea, Henry, and Besche do not teach wherein the nucleic acid sequence of the genetically modified dendritic cell further comprises a miRNA target sequence at its 3’ end.
Brito teaches that one or more miR binding sequences can be incorporated in an mRNA may target the molecule for degradation or reduced translation, provided the miRNA in question is available (e.g., expressed in a target cell or tissue.) In some embodiments, incorporation of one or more miRNA binding sites into an mRNA of the disclosure may reduce the hazard of off-target effects upon nucleic acid molecule delivery and/or enable tissue-specific regulation of expression of a polypeptide encoded by the mRNA page 38, lines 8-19). Brito teaches that miRNA targeting sites for miR-150 can be included in the 3’ UTR of the mRNA to destabilize the mRNA and suppress its expression in B cells (express miR-150) (page 38, lines 20-page 39, line 30).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the genetically modified dendritic cells of the combined teachings of Escors, Rea, Henry, and Besche to include a miR-150 targeting sequence at the 3’ end, as identified by Brito, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Brito teaches that using the miR-150 target sequence in the 3’ UTR will destabilize the mRNA in B cells to provide cell type specific expression (i.e. in dendritic cells but not B cells). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claims 1 and 18-19 above, and further in view of Chiarella et al. (PLoS ONE 9: 1-2. 2014). This is a new rejection substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
The teachings of Escors, Rea, Henry, and Besche are as discussed above. Henry teaches that they transduced dendritic cells in vitro before administering them (page 7231, column 1, paragraph 2-column 2, paragraph 2). It would have been obvious to transduce the cells ex vivo before administering to ensure the lentivirus only infects dendritic cells as in vivo administration of the lentivirus would infect other cell types, limiting the number of transduced dendritic cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Escors, Rea, Henry, and Besche do not teach wherein the nucleic acid construct further comprises a sequence encoding a marker.
Chiarella teaches a dual promoter-based lentiviral vectors that have proven capable of inducing the abundant expression of both transgene and reporter gene in a variety of human hematopoietic cell lines (page 3, paragraph 1 and Figure 1). Chiarella teaches that these vectors are amenable to further development, such as the incorporation selectable genes (page 18, paragraph 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid construct of the ex vivo genetically modified dendritic cells of the combined teachings of Escors, Rea, Henry, and Besche by including a selection gene marker, as identified by Chiarelli, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Chiarella teaches that lentiviral vectors are amenable to further development, such as the incorporation of selectable genes. As selectable gene markers allow for selection of cells that have incorporated the lentiviral construct and removal of cells that did not, it would have been obvious to add a selectable marker to ensure only transduced dendritic cells are administered to a patient, increasing the likelihood of success. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 11, 18-19, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claims 1, 11, and 18-19 above, and further in view of Squadrito et al. (Nature Methods 15: 183-186. 2018. Published January 2018). This is a new rejection substantially similar to a previous rejection of record. Any aspect of Applicant’s traversal that is relevant to the new rejection of record is addressed below.
The teachings of Escors, Rea, Henry, and Besche are as discussed above
The combined teachings of Escors, Rea, Henry, and Besche do not teach wherein the lentiviral vector is bidirectional.
Squadrito teaches that they made bidirectional lentiviral vectors with an SSFV promoter of a therapeutic transgene and a CMV promoter driving expression of GFP to transduce dendritic cells. Squadrito teaches that their bidirectional lentivirus produced expression of both transgenes (abstract and Supp Figure 1 and Methods page 2, column 1, paragraph 4-column 2, paragraph 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid construct of the genetically modified dendritic cells of the combined teachings of Escors, Rea, Henry, and Besche by using a bidirectional lentiviral vector, as identified by Squadrito, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Escors and Squadrito use the same promoters (SFFV and CMV) in the lentivirus and transduce the same cell type (dendritic cells) and Squadrito has successfully reduced to practice that bidirectional lentiviruses can express both transgenes in dendritic cells. As such, it would have been obvious that one could change the monodirectional construct of Escors into a bidirectional construct in the vein of Squadrito. Furthermore, there are only two options for the arrangement of promoter as either monodirectional or bidirectional, and one of ordinary skill would have immediately envisioned the bidirectional option from such a small genus. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed February 11, 2026, are acknowledged.
Applicant argues that the Gregori declaration identifies that regarding the bidirectional promoter, bidirectional promoter systems are technically challenging due to risks including transcriptional competition, silencing, and imbalanced expression between the two transgenes. These issues are exacerbated in primary dendritic cells, which possess antiviral sensing machinery and epigenetic mechanisms that can unpredictably alter transgene expression. Simply applying Squadrito' s architecture to Escors type lentiviral vectors would not have assured stable, coordinated expression of both the antigen and IL-10 transgenes required for the tolerogenic phenotype of the claimed cells. There is no teaching or suggestion in Squadrito regarding tolerogenic programming or induction of antigen-specific Tregs. Accordingly, simply applying the architecture of Squadrito to the method of Escors would not have resulted in a reasonable expectation of success in achieving correct levels of expression of the transgenes recited in the present invention. Squadrito discloses GFP and another trans gene. There is no teaching or suggestion in Squadrito of expression of tolerogenic trans genes such as antigen fusion protein or IL-10. The behaviour of these trans genes in a dendritic cell when
expressed from a bidirectional vector could not have been reasonably predicted to succeed based on the disclosure of Squadrito in combination with Escors, Rea, and Henry (page 14, paragraph 6-page 15, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant argues bidirectional promoter systems are technically challenging due to risks including transcriptional competition, silencing, and imbalanced expression between the two transgenes and these issues are exacerbated in primary dendritic cells, which possess antiviral sensing machinery and epigenetic mechanisms that can unpredictably alter transgene expression, they have not provided any evidence that this is the case.
Furthermore, 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 rejection is based on the combined teachings of Escors, Rea, Henry, Besche, and Squadrito which as stated in the rejection above, teach all of the elements of the rejected claims.
1. Escors teaches dendritic cells be modified to express an antigen in addition to an exogenous transgene that can increase IL-10.
2. Rea teaches dendritic cells can be modified to express the exogenous transgene IL-10.
3. Henry provides the motivation to make and use dendritic cells expressing IL-10
4. Besche teaches that IL-10 can be expressed in a dual transgene lentiviral vector
5. Squadrito successfully reduces to practice that bidirectional vectors with an SSFV promoter of a therapeutic transgene and a CMV promoter driving expression of GFP can transduce dendritic cells
Therefore, one of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Escors and Squadrito use the same promoters (SFFV and CMV) in the lentivirus and transduce the same cell type (dendritic cells) and Squadrito has successfully reduced to practice that bidirectional lentiviruses can express both transgenes in dendritic cells. As such, it would have been obvious that one could change the monodirectional construct of Escors into a bidirectional construct in the vein of Squadrito. Furthermore, there are only two options for the arrangement of promoter as either monodirectional or bidirectional, and one of ordinary skill would have immediately envisioned the bidirectional option from such a small genus. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Furthermore, Applicant is reminded that any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a genetically modified dendritic cell. Furthermore, the Federal Circuit found that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
Claims 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claim 1 above, and further in view of Arunachalam (International Immunology 6: 439-451. 1993). This is a new rejection substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
The teachings of Escors, Rea, Henry, and Besche are as discussed above
The combined teachings of Escors, Rea, Henry, and Besche are silent as to which human invariant chain isoform is used.
However, Arunachalam teaches that there are four human invariant chain forms: p33, p35, p41, and p43 (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid construct of the genetically modified dendritic cells of the combined teachings of Escors, Rea, Henry, and Besche to use p33, p35, p41, or p43 as the human invariant chain, as identified by Arunachalam, to arrive at the instantly claimed invention. It would have been obvious that the invariant chain of the combined teachings of Escors, Rea, and Henry would be one of the four human invariant chain sequences as part of the construct because Arunachalam teaches that these are only four human invariant chain forms (p33, p35, p41, or p43). Therefore, although Escors is silent as to which form is present in their construct, it must be one of the four of instant claim 5. Furthermore, there are only four options for the MHC invariant chains, and one of ordinary skill would have immediately envisioned one of the four options from such a small genus. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claim 1 above, and further in view of Haase et al. (Clinical and Experimental Immunology, 160: 331–339. 2010), as evidenced by Fousteri et al. (Diabetologia 53:1958–1970. 2010). This is a new rejection substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
The teachings of Escors, Rea, Henry, and Besche are as discussed above
Although Escors teaches using the model antigen of OVA and is concerned with treating autoimmune disease, the combined teachings of Escors, Rea, Henry, and Besche do not teach wherein the antigenic peptide or protein is InsB9-23.
Haase teaches that interleukin (IL)-10-treated DCs can protect NOD mice from diabetes development, but only if pulsed with antigenic peptides from human insulin B chain (InsB9–23), an autoantigen, whereas unpulsed DCs had no effect on diabetes development (page 332, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleic acid construct of the genetically modified dendritic cells of the combined teachings of Escors, Rea, and Henry by using InsB9–23 as the antigen fused to the invariant chain, as identified by Haase, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Haase teaches that interleukin (IL)-10-treated DCs can protect NOD mice from diabetes development, but only if pulsed with antigenic peptides from insulin B chain (InsB9–23), whereas unpulsed DCs had no effect on diabetes development. As such, it would have been obvious to use InsB9–23 as the antigen to treat autoimmune diseases such as diabetes. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Fousteri evidences that InsB9–23 has a sequence that is 100% identical to SEQ ID NO: 1 of the instant application (SHLVEALYLVCGERG).
Claims 1 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Escors et al. (Blood 15: 3050-3061. 2008), Rea et al. (Human Immunology 65: 1344–1355. 2004), Henry et al. (J Immunol 181: 7230–7242. 2008), and Besche et al. (The Journal of Gene 12: 231-243. 2010) as applied to claims 1 and 31 above, and further in view of Saeki et al. (J Allergy Clinical Immun 114: 538-543. 2004). This is a new rejection substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
The teachings of Escors, Rea, Henry, and Besche are as discussed above. As stated supra, Escors teaches that tolerance to pathogenic auto-antigens or allergens could be induced by injection of DCs expressing IRF3 or coexpression of transgenes with modulators of DC maturation such as activators IRF3 could suppress immune responses against the transgene (page 3059, column 2, paragraph 1).
The combined teachings of Escors, Rea, Henry, and Besche do not teach wherein the pharmaceutical composition includes a therapeutic agent.
However, Saeki teaches that dexamethasone inhibits TNF-α production which is known to promote dendritic cell maturation while not impacting IL-10 production (page 542, column 2, paragraph 2-page 543, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition of Escors, Rea, Henry, and Besche by including dexamethasone, as identified by Saeki, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to make the modifications with a reasonable expectation of success because Saeki teaches that dexamethasone inhibits TNF-α production which is known to promote dendritic cell maturation while not impacting IL-10 production. As Escors is focused on preventing maturation of their dendritic cells, it would have been obvious to include dexamethasone as it inhibits TNF-α production which is known to promote dendritic cell maturation while not impacting IL-10 production, thus further ensuring the dendritic cells do not mature. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631 /JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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