DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-8, 10-12, and 19-28 are pending.
Claims 1,5,7,19, and 21 are amended.
Claims 19-28 are withdrawn.
Claims 1-8, 10-12 are under examination.
Withdrawn Rejections
Objection to specification.
Objection to Claims.
Applicant’s arguments, see applicant’s remark on page 8, filed 07/09/2025, with respect to the claim 5 have been fully considered and are persuasive. The objection to claim 5 has been withdrawn.
Allowable Subject Matter
Claims 3-4, and 11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance:
Sequence search did not find any prior art that shared 100% identity with the claimed elected species SEQ ID No: 6 of the disclosed invention. The sequence search was further extended to include the species claimed in claims 3-4 (i.e. SEQ ID NO:1-5,21,23-26, and 30-31). The search results yielded no prior art with 100% identity to the claim species in claim 3-4.
Edited Rejections necessitated by Claims Amendment.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim 1-2, 5-6, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Mingozzi et al (WO 2019/154939 A1, with priority of 02/07/2018) in view of Kozak et al ( Nucleic Acids Research, 1984), and Wet et al ( Molecular and Cellular Biology,1987).
Regarding claim 1, Mingozzi et al teach composite transcription regulatory element to drive gene expression in different tissues in a tissue-selective manner. The composite transcription regulatory element comprises hybrid promoters, which are created by fusing at least two promoters to drive gene expression in different tissues. ( See abstract). According to Mingozzi, the composite transcription regulatory elements may combine different tissue-selective enhancers and/or promoters. (See page 18, lines 1-2, See Fig.1B). In one embodiment, Mingozzi et al teach a composite transcription regulatory element containing a combination of the ApoE enhancer, the hAAT promoter ( hAAT is a liver-selective promoter), and the spC5.12 promoter ( spC5.12 is a muscle-selective promoter).(See page 5, lines 13-17). It should be noted that Mingozzi et al use the term Liver-muscle promoter (i.e. LiMP) to refer to the nucleic acid composite comprising the ApoE enhancer, hAAT promoter, and the spC5.12 promoter. The Mingozzi composite nucleic acid regulatory elements contain one copy of ApoE enhancer element, this reads on step (a) of instant claim, and two promoters arranged in tandem wherein at least one of the promoters is hAAT, this reads on step (b) of instant claim. It is noted that the instant claim 1 has been amended to provide a specific orientation for the promoters within the nucleic acid composite, with the hAAT being the downstream promoter relative to the other promoter. However, such amendment does not overcome the current rejection. This is because Mingozzi et al clearly demonstrate that adopting the other orientation, for example, constructing composite nucleic acid regulatory elements comprising of two promoters arranged in tandem, wherein at least one of the promoters is hAAT and the hAAT is being the upstream promoter relative to the other promoter still works. Furthermore, there is no evidence in the instant disclosure that shows adopting one orientation over the other would produce unexpected results. Absent evidence to the contrary and the claim is considered obvious.
Mingozzi et al also do not utilize a start- codon modified hAAT.
Kozak et al teach that the utilization of a downstream ATG codon as a site for the initiation of protein synthesis can be greatly reduced by the presence of an upstream ATG codon in the promoter region. As such, Kozak et al demonstrate that inserting a start codon sequence AUG (i.e. ATG) in the promoter region upstream of the normal AUG start site for the preproinsulin transgene significantly reduces the yields of proinsulin. Kozak et al also teach that the extent to which an upstream AUG codon interferes with gene expression is determined by the sequences surrounding the AUG triplet. ( See abstract, and Fig.1). According to Kozak, the presence of an upstream initiation codon in the promoter region may function as a barrier, diverting ribosomes away from potential initiation sites further downstream, resulting in a significant reduction in translation efficiency from the standard initiation site. ( See Discussion, 1st paragraph, page 3887).
Wet et al used full-length intronless firefly luciferase genes that included differing amounts of 5'- and 3'-untranslated sequence to investigate the expression properties of these genes in mammalian cells. Wet et al demonstrate that deleting a portion of the 5' -untranslated region of the luciferase gene removes an upstream initiation (AUG) codon, resulting in a twofold increase in the level of luciferase expression. (See abstract).
Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Mingozzi, Kozak, and Wet to create a composite nucleic acid regulatory element containing a codon optimize start codon to direct the expression of a therapeutic polypeptide in multiple tissue in a tissue-specific manner. Because Mingozzi et al utilize a composite transcription regulatory element to drive gene expression in different tissues in a tissue-selective manner. Kozak et al demonstrate that inserting a start codon sequence (AUG) in the promoter region upstream of the normal AUG start site for the preproinsulin transgene significantly reduces proinsulin yields. Wet et al teach that deleting a portion of the 5' -untranslated region of the luciferase gene that removes an upstream initiation (AUG) codon results in a twofold increase in the level of luciferase expression. Thus, one would have been motivated to use a composite nucleic acid regulatory element to drive gene expression in different tissues, as disclosed by Mingozzi, as well a start-codon modified regulatory elements to improve the efficiency and the specificity of delivering a therapeutic polypeptide in multiple tissues. There would be a reasonable expectation of success in using a composite nucleic acid regulatory elements and to start-codon modify it, because doing so would increase the efficiency of gene expression, as the presence of an upstream initiation codon relative to the normal initiation-codon would interfere with the translation process of the therapeutic polypeptide and, if not modified, could constitute an absolute barrier, as disclosed by Kozak et al. Some Teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143 (I)(G).
Regarding claim 2, Mingozzi et al teach among the promoters that can be arranged in tandem and included in the composite regulatory element include: TBG promoter, Spc5.12 promote, and others.(See page 4, lines 12-30).
Regarding claim 5, Mingozzi et al state that “ the invention relates to an expression cassette comprising the nucleic acid sequence disclosed herein, and a transgene of interest. The transgene of interest may more particularly be a therapeutic transgene of interest. In specific embodiments, the therapeutic transgene of interest is acid alpha-glucosidase (GAA)”. (See page 5, lines 20-23).
Regarding claim 6, Mingozzi et al demonstrate that an intravenous injection of AAV9 containing the multi-tissue promoter ( i.e. the liver-muscle promoter (LiMP)) and encoding for native GAA is able to drive efficient transgene expression in both liver and muscle tissues.(See Fig. 4B). Mingozzi et al do not teach a recombinant expression cassette that encodes for a therapeutic antibody. However, a person of ordinary skill, in reading Mingozzi et al, would have recognized the value of using Mingozzi’s composite transcription regulatory elements of to drive the expression of a therapeutic transgene encoding antibody or an antigen binding fragment and use that for the treatment of several other diseases. Mingozzi et al state that “Based on their favorable safety and efficacy profile, dual promoters may provide a significant advantage in the development of gene-based therapies for the treatment of several other diseases with systemic, multiple organ involvement and early lethality”. (See Conclusion page 62, lines 13-15). Thus, it would have been obvious to a person with ordinary skill in the art to utilize the composite transcription regulatory elements to drive the expression of therapeutic antibody in an attempt to provide gene-based therapies for the treatment of a variety of diseases. It has been held that "a person with 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 the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Regarding claim 7, Mingozzi et al teach LiMP composite, a nucleic acid regulatory elements that contains the ApoE enhancer, the hAAT liver promoter, and the spC5.12 muscle promoter. Sequence search results show that spC5.12 promoter found in the Mingozzi LiMP composite has 100% sequence identity with SEQ ID 29 of the instant claim. ( See Mingozzi’s SEQ ID NO.6, and the “SCV sequence search results” attachment) .
Regarding claim 8, 10, and 12, Mingozzi et al state that “ the invention relates to a vector comprising the expression cassette disclosed herein. Said vector may be, in particular a viral vector. Representative viral vectors include, without limitation, adenovirus vectors, retrovirus vectors, lentivirus vectors and AAV vectors. In a particular embodiment, the viral vector is an AAV vector, such as an AAV vector comprising an AAV8 or AAV9 capsid”.
Response to Arguments
Applicant's arguments filed 07/09/2025 have been fully considered but they are not
persuasive.
Applicants argue that neither Kozak or De Wet does teach or suggest the elimination of AUG sites in a downstream hAAT promoter in the context of composite regulatory elements. Hence, there is no connection between the Kozak reference or the De Wet reference to the art of creating composite regulatory elements (e.g. promoters), including as taught in Mingozzi et al.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In addition, applicants argue that Kozak discovered that the presence of multiple upstream AUG sites does not always reduce overall protein production, rather, whether there is a reduced effect depend on the sequences surrounding the initiation start sites. Applicants also argue that eliminating the 5' UTR from the De Wet reference was not to remove the upstream AUG codon, but rather to generate a full-length P. pyralis luciferase cDNA clone.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the argument that Kozak et al teach that the sequences surrounding the initiation start sites, rather than the presence of an upstream AUG, is what control the efficiency of translation, is not accurate. Because Kozak et al utilizing three modified plasmids (p255/2A, P255/15A, and P255/16A, each with an upstream AUG triplet that was out of-frame with respect to the coding sequence of preproinsulin, and the sequence surrounding the AUG varies slightly amongst the three plasmids) demonstrated that inserting a start codon sequence AUG (i.e. ATG) in the promoter region upstream of the normal AUG start site for the preproinsulin transgene significantly reduces the yields of proinsulin from all plasmids ( i.e. P255/2A, P255/15A, and P255/16A). ( See Fig.3). Kozak et al further go on to explain that the sequences surrounding an upstream AUG codon can also interfere with gene expression. ( See section “ Synthesis of Proinsulin from Modified Plasmids that Have an Upstream, Out-of Frame ATG Triplet” on pages 3880-3882). Taken together, the teachings of Kozak et al demonstrate that inserting a start codon sequence (AUG) in the promoter region upstream of any transgene’s AUG start site may interfere with the translational yields.
Turning to Applicants argument regarding De Wet et al, the argument is also not found persuasive, because regardless of what was the purpose of the experiment was, De Wet et al clearly state “ that Deleting a portion of the 5' -untranslated region of the luciferase gene removed an upstream initiation (AUG) codon and resulted in a twofold increase in the level of luciferase expression”. (See abstract). Therefore, an ordinary skill in the art who come across Kozak et al and De Wet et al would recognize that placing two promoters in tandem would increase the probability of introducing an upstream AUG relative to the transgene’s AUG start site, the presence of which would probably reduce the translational yields of the transgene. The ordinary artisan is able to know from the common general knowledge in the art and from the teachings of Kozak and De Wet that the presence of an upstream AUG in the promoter regions can interfere with the translational efficiency of the transgene. Therefore, the person skilled in the art would prefer to eliminate any upstream AUG in the promoter regions that are placed in tandem in order to enhance the translational efficiency of the transgene.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638