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 .
Applicant’s arguments and amendments of June 10, 2026, are entered.
Claims 18 and 38 have been amended.
Claims 47-51 are new.
Claims 30-31 and 44-45 have been canceled.
Status of Claims
Claims 18, 29, 32-34, 36-38, and 46-51 are pending.
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 18, 29, 32-34, 36-38, and 46-51 are rejected under 35 U.S.C. §103 as being unpatentable over Kingsman et al. [WO 2008 071959 A1], in view of Wu et al. [Adeno-associated virus serotypes: vector toolkit for human gene therapy, Molecular Therapy, 2006], in view of Alberini and Bear (Hereinafter Alberini) [US 2003 166555 A1], in view of Kelly and Russell (Hereinafter Kelly) [MicroRNAs and the regulation of vector tropism, Molecular Therapy, 2009], in view of Hui et al. [Systemic elimination of de novo capsid protein synthesis from replication-competent AAV contamination in the liver, Human Gene Therapy, 2011], in view of Monsonego [US Pat. 10,117,895, 2013], in view of Lkhagvasuren et al. [A comparative analysis of constitutive promoters located in adeno-associated viral vectors, PLoS One, 2013], in view of Lagos-Quintana et al. [Identification of tissue-specific microRNAs from mouse, Current Biology, 2002].
For claim 18, Kingsman et al. generally teaches a gene construct that contains a nucleotide sequence that encodes a mammalian insulin-like growth factor (IGF-1) and at least one target sequence of microRNA that is expressed in a tissue in which expression of IGF-1 resulting from the gene construct is to be prevented [pg. 7 ¶ 4-5]. Kingsman et al. specifically discloses the microRNAs are miR-1b/d, miR-133, or miR-206 [pgs. 6 and 50]. Kingsman et al. further teaches that the nucleotide sequence is operably linked to a ubiquitous promoter [pg. 14 ¶ 3]. Lastly, Kingsman et al. teaches that the delivery vector can be a retroviral vector or a lentiviral vector [pg. 9 ¶ 2, pg. 11 ¶ 2]. However, Kingsman et al. does not disclose the specific vector as being AAV8. For this limitation Wu et al. provides that different serotypes have a propensity for different types of tissues [Abstract]. More specifically, AAV8, as taught by Wu et al., displays a propensity for liver transduction. Additionally in Table 1, Wu et al. also discloses that AAV8 has a propensity for both the heart and the pancreas.
For the claim 18 limitation where the amino acid sequence has at least 97% identity to SEQ ID NO: 23, Alberini et al. discloses an amino acid sequence for human IGF-1 that is 100% identical to Applicant’s SEQ ID NO: 23 where the disclosed sequence is the IGF-1 preprotein, isoform 2 (listed as SEQ ID NO: 8 in Alberini et al.) [¶ 0069, 0105-0106].
For the limitation where at least four copies of microRNA-122a target sequence and at least 4 copies of microRNA-1 target sequence, Kelly et al. teaches that incorporating miRNA target elements for multiple miRNAs within a single viral vector to enhance tissue-specific silencing and/or restrict vector tropism [Abstract, Range of Target Elements ¶ 1]. Furthermore, Kelly et al. teaches that multiple copies of miRNA target elements may be incorporated into a vector [Range of Target Elements]. In addition, Hui et al. specifically teaches an AAV helper construct comprising four copies of a liver-specific miR-122 target sequence and four copies of a second tissue-specific miRNA target sequence demonstrating the use of multiple miRNA target copies within a single AAV construct [Figure 1]. Based on this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kingsman et al. that generally disclosed a vector construct containing a IGF-1 sequence coupled with miR-1 target sequence with the additional teachings of both Kelly and Hui et al. where both references disclosed that multiple target sequences were possible. In addition, Kelly taught that four tandem copies of a miRNA target sequence provided greater silencing than one or two copies while also recognizing any number beyond four does not necessarily further increase silencing [Designing the regulatory insert]. Therefore, there would have been a reasonable expectation of success for a person of ordinary skill in the art to modify the teachings to Kingsman et al. to construct a vector that contained a nucleic acid sequence where the IGF-1 sequence in Kingsman was substituted with another known IGF-1 sequence coupled with at least 4 copies of miRNA-1 and miRNA-122 given that both Kelly and Hui et al. teach that that multiple target sequences can be included in a single vector and that multiple copies of the chosen miRNA target sequences, including up to 4, work better than two or one copies in silencing gene expression [Id.]. Furthermore, Table 1 listed in Kelly discloses that miR-122a was specific to the liver and miRNA-1 was specific to cardiac and skeletal muscle.
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kingsman et al. where it discloses a viral vector, to include a retrovirus, that contained an IGF-1 and mircoRNA target sequence was operably linked with a ubiquitous promoter with Wu et al. that discusses the various AAV vectors with Alberini that discloses an IGF-1 sequence that is identical to Applicant’s claimed SEQ ID NO: 23 with the further teachings of both Kelly and Hui et al. that disclose that different microRNAs can be included in the same vector for suppressing transgene expression in multiple tissues as well multiple copies of two different microRNAs were included where the multiple copies enhanced suppression of targeted transgene expression related to a specific tissue depending on what microRNA was chosen. Therefore, a person of ordinary skill would have had a reasonable expectation of success to combine above teachings into a construct where a person of ordinary skill would have chosen the appropriate AAV serotype based on the tissue to be targeted where the viral vector contained an IGF-1 amino acid sequence that could be easily substituted for another IGF-1 amino acid sequence with operably linked microRNAs that were chosen based on the specific tissues being targeted and that multiple copies of each microRNA could be incorporated within a single vector and that the vector could also contain multiple types of microRNAs for targeting different tissue types such as one target sequence that targets the liver and/or pancreas and another microRNA sequence that targets skeletal and/or cardiac muscle.
Furthermore, MPEP § 2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. V. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)." "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig saw puzzle." 325 U.S. at 335, 65 USPQ at 301.)." When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. $2144.06.
For claim 29 where the nucleotide sequence encoding IGF-1 is SEQ ID NO: 3, Monsonego teaches a genetically modified T cells constitutively expressing a polypeptide of interest where the polypeptide includes IGF-1 and that the nucleic acid sequence is 100% identical to SEQ ID NO: 3 [See NM_001111284, col. 19, line 13 SEQ ID NO: 52]. Here, it would have been prima facie obvious to one of ordinary skill in the art to substitute a first nucleic acid sequence encoding IGF-1, as disclosed by Kingsman et al, with a second nucleic acid sequence encoding IGF-1, to wit, SEQ ID NO:3, as disclosed by Monsonego and GenBank NM_001111284.1, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. $2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. V. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)." "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.)." When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. $2144.06. An artisan would be motivated to substitute a first nucleic acid sequence encoding IGF-1 with a second nucleic acid sequence encoding IGF-1, to wit, SEQ ID NO:3, because those of ordinary skill in the art previously recognized the existence of SEQ ID NO:3 to encode IGF-1 and Monsonego et al disclosed the use of SEQ ID NO:3 in an expression vector to express IGF-1 in the artisan's host cell of interest.
For claim 32 where the gene construct comprises four copies of the microRNA-122 target sequence and four copies of the microRNA-1 target sequence, see the analysis for claim 18.
For claim 33 where the promoter is a constitutive promoter, Kingsman et al. discloses that the promoter can be a constitutive promoter with the example the promoter may be a heterologous promoter such as another viral promoter, for example a CMV promoter [Para starting with “A minimal lentiviral genome for use in the present invention will therefore…”].
For claim 34 where the constitutive promoter is a CAG promoter, Lkhagvasuren et al. teaches that CAG, along with two other promoters, demonstrated an advantage in sustaining stable gene expression over longer periods versus CMV being prone to silencing over time [Introduction ¶ 1]. Furthermore, Lkhagvasuren et al. also teaches that CAG is a constitutive promoter [Id.].
For claim 37 where a pharmaceutical composition comprising an AAV vector of claim 18 and one or more pharmaceutically acceptable excipients or vehicles, Kingsman et al. teaches that the composition, i.e. viral vector construct, may also include a pharmaceutical composition for treating individuals by gene therapy and that the pharmaceutical composition can contain a pharmaceutically acceptable carrier, excipient, diluent [Pharmaceutical Compositions ¶ 1-3].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kingsman et al. where it discloses a viral vector, to include a retrovirus, that contained an IGF-1 and mircoRNA target sequence was operably linked with a ubiquitous promoter with Wu et al. that discusses the various AAV vectors with Alberini that discloses an IGF-1 sequence that is identical to Applicant’s claimed SEQ ID NO: 23 with the further teachings of both Kelly and Hui et al. that disclose that different microRNAs can be included in the same vector for suppressing transgene expression in multiple tissues as well multiple copies of two different microRNAs were included where the multiple copies enhanced suppression of targeted transgene expression related to a specific tissue depending on what microRNA was chosen with the additional teachings of Lkhagvasuren et al. where the authors disclosed that CAG, a constitutive promoter, had the advantage of sustained stable gene expression over longer periods of time versus CMV which was prone to silencing over time with the additional teachings of Kingsman et al. that discloses combining the viral vector construct into pharmaceutical composition that can contain a pharmaceutical acceptable carrier, excipient, and/or diluent. Based on this, a person of ordinary skill would have had a reasonable expectation of success to combine above teachings into a construct where a person of ordinary skill would have chosen the appropriate AAV serotype based on the tissue to be targeted where the viral vector contained an IGF-1 amino acid sequence that could be easily substituted for another IGF-1 amino acid sequence with operably linked microRNAs that were chosen based on the specific tissues being targeted and that multiple copies of each microRNA could be incorporated within a single vector and that the vector could also contain multiple types of microRNAs for targeting different tissue types such as one target sequence that targets the liver and/or pancreas and another microRNA sequence that targets skeletal and/or cardiac muscle where the person of ordinary skill would also have recognized the benefits of choosing a constitutive promoter, and more specifically, a CAG promoter as the promoter to be operably linked to the IGF-1 nucleic acid sequence given that CAG was shown to sustain stable gene expression for longer periods of time compared to more conventional constitutive promoters such as CMV. Furthermore, there would have been a reasonable expectation of success for a person of ordinary skill to recognize the additional teachings of Kingsman et al. to include the viral vector construct into a pharmaceutical composition that also included a pharmaceutical acceptable carrier, excipient, and/or diluent.
For claim 38, please see the analysis for claim 18 coupled with the additional teachings of Lkhagvasuren et al. where the authors disclosed that certain constitutive promoters were more advantageous given these promoters were able to stably sustain gene expression over longer periods of time, i.e. CAG [Introduction ¶ 1], over more conventional constitutive promoters such as CMV.
For claims 46, please see the analysis for claim 18 where it discusses the rational of why a person of ordinary skill would have chose multiple copies of both miR-122 and miR-1.
For claims 47 and 48 where microRNA-122 target sequence comprises SEQ ID NO: 8 and microRNA-1 comprises SEQ ID NO: 15, Lagos-Quintana et al. teaches three different mouse miRNA-122 sequences that are identical to Applicant’s SEQ ID NO: 8 [Table 1. Mouse miRNA sequences identified by cloning from distinct mouse tissues. Lagos-Quintana also teaches three target sequences of miR-1 (SEQ ID NO: 15) where 21 of the 22 nucleotides of SEQ ID NO: 15 are shared by all miR-1 disclosed target sequences [See Table 1]. it would have been obvious to one of ordinary skill in the art to substitute a first miR-122 target sequence comprising SEQ ID NO:8, as taught by Xie et al, with a second miR-122 target sequence, i.e. a miR-122a target sequence consisting of SEQ ID NO:8, as taught by Lagos-Quintana et al, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. $2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. V. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)." "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.)." When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. $2144.06. It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product is not of innovation but of ordinary skill and common sense." The ordinary artisans previously recognized that there is a finite list of three known options of miR-122 target sequences.
For claims 49 and 50, see the analysis for claims 47 and 48 being rejected listed above.
For claim 51 where a pharmaceutical composition comprising the AAV vector of claim 38 and one or more pharmaceutically acceptable excipients or vehicles, Kingsman et al. teaches that the composition, i.e. viral vector construct, may also include a pharmaceutical composition for treating individuals by gene therapy and that the pharmaceutical composition can contain a pharmaceutically acceptable carrier, excipient, diluent [Pharmaceutical Compositions ¶ 1-3].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kingsman et al. where it discloses a viral vector, to include a retrovirus, that contained an IGF-1 and mircoRNA target sequence was operably linked with a ubiquitous promoter with Wu et al. that discusses the various AAV vectors with Alberini that discloses an IGF-1 sequence that is identical to Applicant’s claimed SEQ ID NO: 23 with the further teachings of both Kelly and Hui et al. that disclose that different microRNAs can be included in the same vector for suppressing transgene expression in multiple tissues as well multiple copies of two different microRNAs were included where the multiple copies enhanced suppression of targeted transgene expression related to a specific tissue depending on what microRNA was chosen with the additional teachings of Lkhagvasuren et al. where the authors disclosed that CAG, a constitutive promoter, had the advantage of sustained stable gene expression over longer periods of time versus CMV which was prone to silencing over time with the additional teachings of Kingsman et al. that discloses combining the viral vector construct into pharmaceutical composition that can contain a pharmaceutical acceptable carrier, excipient, and/or diluent. Based on this, a person of ordinary skill would have had a reasonable expectation of success to combine above teachings into a construct where a person of ordinary skill would have chosen the appropriate AAV serotype based on the tissue to be targeted where the viral vector contained an IGF-1 amino acid sequence that could be easily substituted for another IGF-1 amino acid sequence with operably linked microRNAs that were chosen based on the specific tissues being targeted and that multiple copies of each microRNA could be incorporated within a single vector and that the vector could also contain multiple types of microRNAs for targeting different tissue types such as one target sequence that targets the liver and/or pancreas and another microRNA sequence that targets skeletal and/or cardiac muscle where the person of ordinary skill would also have recognized the benefits of choosing a constitutive promoter, and more specifically, a CAG promoter as the promoter to be operably linked to the IGF-1 nucleic acid sequence given that CAG was shown to sustain stable gene expression for longer periods of time compared to more conventional constitutive promoters such as CMV. Furthermore, there would have been a reasonable expectation of success for a person of ordinary skill to recognize the additional teachings of Kingsman et al. to include the viral vector construct into a pharmaceutical composition that also included a pharmaceutical acceptable carrier, excipient, and/or diluent.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant arguments are directed to lack of reasonable expectation of success and lack of direction to combine.
Examiner appreciates Applicant’s arguments. However, Applicant’s arguments are not persuasive.
To start, the withdrawal of the prior enablement rejection does not establish that the claimed combination was unpredictable for purposes of 35 U.S.C. §103 given that enablement under 35 U.S.C. §112(a) and reasonable expectation of success under §103 are distinct inquiries. Here, the cited references provide working teachings of the claimed components and their intended functions. In particular, Hui et al. demonstrates the incorporation of miR-122 target sequences into an AAV vector to achieve tissue-specific suppression, while Kingsman et al. and Kelly teach the use of microRNAs target sequences, to include miRNA-1 associated target sequences, are capable of regulating viral expression. Alberini provides a substitute IGF-1 sequence, Lkhagvasuren et al. provides a strong rational for the use of a constitutive promoter when combined with adeno-associated viral vectors, more specifically CAG, and Lagos-Quintana provides known sequences associated with the miRNA-122a and miRNA-1. Thus, the proposed combination employs known elements according to their established functions and would have provided a reasonable expectation of success. In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). Additionally, the references need not expressly direct a skilled artisan to combine every element in the precise manner recited. Here, the known use of constitutive promoters to express heterologous proteins and the demonstrated use of tissue-specific miRNA target sequences combined with the teachings that multiple miRNAs could be incorporated into a single vector and that these miRNAs could be included as a single, double or quadruple copy in order to regulate expression provide the needed rational.
Furthermore, Applicant’s argument regarding unexpected results are not persuasive because the asserted results are directed to treatment of diabetes type 1 and type2. However, the claims are silent as to any therapeutic use or treatment of diabetes. Claims 18 and 38 are both directed to an AAV vector defined by particular structural and genetic features that does not require the administration of the vector to a subject, treatment of diabetes, particular cell types located withing a specific organ, or achieve any particular therapeutic result. Evidence that a particular construct provides an advantageous result in treating diabetes does not demonstrate an unexpected property that is commensurate with the scope of the claimed invention. It merely states an unclaimed therapeutic use and result that does not establish the claimed combination of vector components produce that purported results. Because of this, claims 18, 29, 32-34, 36-38, and 46-51 are rejected under §103 for the above stated reasons.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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