DETAILED ACTION
Claims 1-12, and 14-21 are pending and under examination in this application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/7/24 and 9/26/24 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 and 14-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 1 recites several limitations preceded by the phrase “preferably” or “more preferably”- see part (iii) which recites in part, “preferably the mutation is a mutation from T to C or G or A….”, “more preferably a T to C mutation”, “preferably, the mutant promoter increase the expression of a gene of interest…..”, “more preferably, the mutant promoter is a constitutive promoter…..”, and “preferably the mammal is a human…..”. In all these instances, the word “preferably” renders the claim indefinite as it is unclear whether the limitations following the “word” preferably are a required element of the invention or simply one example of a species which may be part of the invention. In addition, claim 1 also recites several additional limitations preceded by “e.g.”, which is Latin for “for example”. The phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). As such, the metes and bounds of the claim cannot be determined. Claims 2-12, and 14-21 depend on claim 1 and thus are included in this rejection.
In addition, independent claim 1 is further indefinite in the recitation that the nucleotide sequence has been obtained by substitution, deletion or addition of “one or several” nucleotides. The term “several” is a relative term of degree with no specific set meaning in either the prior art nor the as filed specification. As such, it is unclear how many nucleotides are encompassed by the term “several”. In addition, as claim 2, which depends on claim 1, recites that the nucleotide sequence differs from SEQ ID NOS 1-3 by “one or several” nucleotide substitutions, deletions “and/or” deletions”, it is unclear whether the “one or several” nucleotides that have been substituted, deleted or added in claim 1 refers to the number of nucleotides modified in total, or to the number of nucleotides modified individually per substitution, deletion or addition since the “and/or” in claim 2 suggests that the nucleotide sequence could include a substitution, a deletion, and an addition or “several” nucleotides. Thus, the metes and bounds of the modifications to the nucleotide sequence comprising a mutant promoter as set forth in claims 1 and 2 cannot be determined thus rendering the claims indefinite. Claims 3-12 and 14-21 depend on claim 1 and thus are included in this rejection.
Dependent claims 2-8, 11, 14-17, and 19 are further indefinite for multiple recitations of limitations preceded by “preferably” or “e.g.” or “in particular”. As above, it is unclear whether these limitations are required elements of the claims or are simply presented as potential embodiments of the broader of a recited element or step. In addition, claims 4, 7, and 15-16 include recitations of limitations surrounded by parentheses, including “ (e.g., 2-6)” or “(e.g., 2-4)” in claims 4 and 7, “ (preferably, heart, liver, muscle)” and “(including the brain and spinal cord)” in claim 15 and similar instances of parentheses in claim 16. The use of the parentheses further renders the claims indefinite as it is again unclear whether the elements in the parentheses are intended to further limit the claims or whether the elements in the parentheses are simply examples of potential embodiments. Thus, the metes and bounds of claims 2-8, 11, 14-17, and 19 cannot be determined.
Claims Interpretation
In the interests of compact prosecution, the following broadest reasonable claim interpretation has been applied to claims 1-12, and 14-21: all limitations preceded by “preferably”, “more preferably”, or “e.g.” and all limitations within parentheses are not interpreted as being required elements of these claims, but rather have been interpreted as particular embodiments of certain elements encompassed by the claims but not limited thereto. In additional, it is noted that limitations following the word “optionally” are further not considered to be required as these limitations may or may not be included in this invention as claimed.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12 and 14-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims broadly recite a genus of mutant promoters comprising a polynucleotide selected from a group consisting of “ (i) a polynucleotide of SEQ ID NO: 4. (ii) a polynucleotide having at least 95%, 96%, 97%, 98%, 99%, 99.5% identity to SEQ ID NO: 4. (iii) a polynucleotide obtained by substitution, deletion or addition of one or several nucleotides to the polynucleotide of SEQ ID NO: 4, and wherein the polynucleotide has a mutation at positions 562-572 of SEQ ID NO:4 or at positions corresponding thereto”. The genus of mutant promoters as claimed in for example independent claim 1 are disclosed in the specification and recited in the claim as having promoter activity and further disclosed and claimed as being capable of increasing the expression of a gene of interest in a mammalian peripheral tissue or central nervous tissue, and more narrowly in the heart, liver or brain. Dependent claim 2 further limits the promoter to a nucleotide sequence selected from SEQ ID NOS 1-3, or a nucleotide sequence differing from one of these sequences by one or several nucleotide substitutions, deletions and/or additions and having “equivalent activity”. Thus, at minimum, the claims as written read on a large genus of mutant nucleotide sequences which differ from the synthetic promoter sequence disclosed as SEQ ID NO:4 by anywhere from one to 31 nucleotides- where 31 nucleotide differences is equivalent to 95% homology to SEQ ID NO:4, or more than 31 nucleotides depending on the breadth of substitutions, deletions, or additions encompassed by “several” mutations using one or more of these mechanisms, and which maintain at least promoter activity, or increased promoter activity compared to SEQ ID NO:4, or “equivalent activity” compared to SEQ ID NOS 1-3.
A patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Further, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features if there are any. See University of Rochester, 358 F.3d at 927, 69USPQ2d at 1895. Applicant must instead convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.
The specification fails to provide adequate guidance for the genus of mutant nucleotide sequences based on SEQ ID NO:4 as discussed above which exhibit promoter activity, and more particularly promoter activity resulting in increased expression in any mammalian cell compared to the activity of SEQ ID NO:4. The specification further fails to provide adequate guidance for the genus of mutant nucleotide sequences based on SEQ ID NOS 1, 2, or 3, which have “equivalent” promoter expression activity compared to SEQ ID NOS 1, 2, or 3. While the specification generically recites the broad language recited in the instant claims, the specification does not describe any specific mutations, such as substitutions, deletions, or additions to SEQ ID NO:4, or to SEQ ID NOS 1, 2, or 3, which either do not affect promoter activity, or which increase promoter activity other than the mutant sequences set forth in one of SEQ ID NOS 1, 2, and 3. The specification discloses that SEQ ID NO:4 is a synthetic promoter sequence which comprises a CMV early enhancer operably linked to the chicken beta-actin promoter, referred to as a CA promoter in the specification, which has been further operably linked at the 3’ end to intronic sequence identified as nucleotides 62804-62890 from the human TATA box binding protein associated factor 1 (TAF1). The specification discloses that this sequence, SEQ ID NO:4, has promoter activity and can be used in an expression vector to drive the expression of a gene of interest in mammalian cells. The specification also provides working examples which disclose a nucleotide substitution of a single nucleotide at position 568 of SEQ ID NO:4 where the T at position 568 is substituted for a C, A, or G nucleotide, identified as SEQ ID NOS 1, 2, and 3 respectively. Each of these single nucleotide acid substitutions at position 568 of SEQ ID NO:4 result in a promoter which the working examples demonstrate has increased expression activity of an operably linked gene in BHK-21 hamster kidney fibroblast cells compared to the activity of the parent promoter SEQ ID NO:4. The working examples also demonstrate that intravenous injection of an AAV vector, rscAAV9-CAR-MutC-Gluc, which comprises SEQ ID NO:1, to mice induces significantly elevated expression of Gluc in heart, liver, and brain compared to SEQ ID NO:4. In addition, it is noted that the applicant further tested an additional AAV9 encoding GAA operably linked to the promoter of SEQ ID NO:1 and demonstrated that intravenous injection of this vector into GAA -/- mouse model of Pompe disease resulted in increased expression of GAA and increased survival of these model mice. As discussed above, all of these working example use a specific single substitution of T nucleotide at position 568 of the synthetic promoter disclosed as SEQ ID NO:4. The specification does not disclose the effects of any other specific substitutions of any other nucleotide other than the T at position 568, including any other position within nucleotide positions 562-572 of SEQ ID NO:4. The specification further does not describe any specific deletion or addition within that particular sequence within SEQ ID NO:4, nor disclose the effects of any such mutations. Likewise, the specification further does not disclose the effects of any deletion or addition outside this region, or any combination of substitutions, deletions, and additions both within and outside of the region on the activity of SEQ ID NO:4. In particular, the specification does not disclose any mutations that can be combined with the disclosed substitution at position 568 as set forth in SQ ID NOS 1, 2, and 3 that do not change the activity of these mutant promoter sequences, i.e. the additional mutations result in a promoter with equivalent promoter activity to SEQ ID NOS 1, 2, or 3. Thus, of the large genus of mutant promoter sequences encompassed by the claims, the specification only provides adequate written description for a single substitution of the T at position 568 of SEQ ID NO:4.
The following guidance provided in MPEP 2163 is informative. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. In other words, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See for example Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]without such disclosure, the claimed methods cannot be said to have been described."). Furthermore, written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattana sin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996). While it has been held that what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.
As such, based on the analysis of the teachings of the specification provided above, and the court acknowledged standards for adequate written description and for establishing possession of a claimed invention, the specification fails to provide a description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of any of the claimed genus of mutant promoters based on SEQ ID NO:4 other than SEQ ID NOS 1, 2, and 3.
It is also noted that at the time of filing, the prior art teaches that the effects of mutations on promoter sequences cannot be determined a priori, and requires experimental validation. Patwardhan et al., for example, discloses the mutational analysis of one bacteriophage promoter and three different mammalian promoters, including the CMV promoter, and shows that not only did the majority of mutations negatively affect promoter activity, but that the few instances of increased activity due to a single point mutation were not predicted by particular structural elements present in those promoters (Patwardhan et al. (2009) Nat. Biotech., Vol. 27(12), 1173-1175, see Figures 1 and 2). Patwardhan et al. further demonstrates that combining mutations led to unpredictable effects in expression activity of the promoter based on the effects of each mutation separately (Patwardhan et al., Figure 1). In the instant case, the synthetic promoter, as discussed above, combines the enhancer sequence from the CMV promoter, sequence from the chicken beta-actin promoter, and intronic sequence from the TAF1 gene. Patwardhan et al. showed that mutations to the CMV promoter sequence are unpredictable and largely negatively impact activity. The prior art further does not disclose the effects of any or all mutations to the chicken beta promoter. Finally, the preferred site of mutations disclosed by the specification, nucleotides 562-572, is within the intronic sequence, positions 62804-62890, from the human TAF1 gene. The specification is silent as to the activity of this 87 nucleotide intronic sequence, or more specifically the portion of this sequence identified as nucleotides 562-572 of SEQ ID NO:4. At most, the prior art at the time of filing teaches that intron 32 of the human TAF1 gene is the largest intron, 29,932 bp, in the TAF1 gene, and may possibly include a neuron-specific cis-regulatory element based on the effect of transposon insertion into this intron (Makino et al. (2007) Am. J. Hum. Genet., Vol. 80, 393-406, see pages 403-404). However, neither Makino, nor the prior art as a whole provides any teachings regarding a cis-regulatory element within positions 62804-62890 of the TAF1 gene intron 32 sequence, nor do they describe the effects of any mutations in this sequence on the activity of a synthetic promoter which comprises such sequence. Thus, the prior art of record establishes the unpredictability of the effects of introduced mutations on mammalian promoter activity, and is further silent as to any gene regulatory elements present within nucleotides 62804-62890 of the TAF1 gene intron 32, and or its effects, unmutated or mutated, on the activity of a heterologous promoter.
As such, the generation of functional promoter mutants, particularly mutants with increased expression activity, was not considered predictable at the time of filing, and the knowledge and level of skill in the art at the time of filing would not have permitted the ordinary artisan to immediately envisage the genus of claimed mutant promoters based on the sequence of SEQ ID NO:4 with promoter activity from the generic description provided by the specification. In view of these considerations, a skilled artisan would not have viewed the teachings of the specification as sufficient to show that the applicant was in possession of the claimed invention.
Claims 1-12 and 14-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a mutant synthetic promoter sequence with the nucleotide sequence set forth in SEQ ID NO:1, 2, or 3, an expression construct comprising said mutant synthetic promoter operably linked to a nucleotide sequence encoding GAA, an AAV virus vector, a host cell comprising said mutant synthetic promoter sequence, said expression construct, or said AAV virus vector, and methods of treating a subject having Pompe disease or having acid glucosidase deficiency comprising administering said AAV virus vector, does not reasonably provide enablement for any mutant synthetic promoter sequence based on SEQ ID NO:4 as claimed, or the use of such a mutant synthetic promoter in any vector to drive expression of any gene including GAA in vitro or in vivo, or more particularly for the treatment of acid glucosidase deficiency, including Pompe disease in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The claims broadly recite genus of mutant promoters comprising a polynucleotide selected from a group consisting of “ (i) a polynucleotide of SEQ ID NO: 4. (ii) a polynucleotide having at least 95%, 96%, 97%, 98%, 99%, 99.5% identity to SEQ ID NO: 4. (iii) a polynucleotide obtained by substitution, deletion or addition of one or several nucleotides to the polynucleotide of SEQ ID NO: 4, and wherein the polynucleotide has a mutation at positions 562-572 of SEQ ID NO:4 or at positions corresponding thereto”. The genus of mutant promoters as claimed in for example independent claim 1 are disclosed in the specification and recited in the claim as having promoter activity and further disclosed and claimed as being capable of increasing the expression of a gene of interest in a mammalian peripheral tissue or central nervous tissue, and more narrowly in the heart, liver or brain. Dependent claim 2 further limits the promoter to a nucleotide sequence selected from SEQ ID NOS 1-3, or a nucleotide sequence differing from one of these sequences by one or several nucleotide substitutions, deletions and/or additions and having “equivalent activity”. Thus, at minimum, the claims as written read on a large genus of mutant nucleotide sequences which differ from the synthetic promoter sequence disclosed as SEQ ID NO:4 by anywhere from one to 31 nucleotides- where 31 nucleotide differences is equivalent to 95% homology to SEQ ID NO:4, or more than 31 nucleotides depending on the breadth of substitutions, deletions, or additions encompassed by “several” mutations using one or more of these mechanisms, and which maintain at least promoter activity, or increased promoter activity compared to SEQ ID NO:4, or “equivalent activity” compared to one of SEQ ID NOS 1-3.
The specification fails to provide adequate guidance for the genus of mutant nucleotide sequences based on SEQ ID NO:4 as discussed above which exhibit promoter activity, and more particularly promoter activity resulting in increased expression in any mammalian cell compared to the activity of SEQ ID NO:4. The specification further fails to provide adequate guidance for the genus of mutant nucleotide sequences based on SEQ ID NOS 1, 2, or 3, which have “equivalent” promoter expression activity compared to SEQ ID NOS 1, 2, or 3. While the specification generically recites the broad language recited in the instant claims, the specification does not describe any specific mutations, such as substitutions, deletions, or additions to SEQ ID NO:4, or to SEQ ID NOS 1, 2, or 3, which either do not affect promoter activity, or which increase promoter activity other than the mutant sequences set forth specifically in SEQ ID NOS 1, 2, and 3. The specification discloses that SEQ ID NO:4 is a synthetic promoter sequence which comprises a CMV early enhancer operably linked to the chicken beta-actin promoter, referred to as a CA promoter in the specification, which has been further operably linked at the 3’ end to intronic sequence identified as nucleotides 62804-62890 from the human TATA box binding protein associated factor 1 (TAF1). The specification discloses that this sequence, SEQ ID NO:4, has promoter activity and can be used in an expression vector to drive the expression of a gene of interest in mammalian cells. The specification also provides working examples which disclose a nucleotide substitution of a single nucleotide at position 568 of SEQ ID NO:4 where the T at position 568 is substituted for a C, A, or G nucleotide, identified as SEQ ID NOS 1, 2, and 3 respectively. Each of these single nucleotide acid substitutions at position 568 of SEQ ID NO:4 result in a promoter which the working examples demonstrate has increased expression activity of an operably linked gene in BHK-21 hamster kidney fibroblast cells compared to the activity of the parent promoter SEQ ID NO:4. The working examples also demonstrate that intravenous injection of an AAV vector, rscAAV9-CAR-MutC-Gluc, which comprises SEQ ID NO:1, to mice induces significantly elevated expression of Gluc in heart, liver, and brain compared to SEQ ID NO:4. In addition, it is noted that the applicant further tested an additional AAV9 encoding GAA operably linked to the promoter of SEQ ID NO:1 and demonstrated that intravenous injection of this vector into GAA -/- mouse model of Pompe disease resulted in increased expression of GAA and increased survival of these model mice. As discussed above, all of these working example use a specific single substitution of T nucleotide at position 568 of the synthetic promoter disclosed as SEQ ID NO:4. The specification does not disclose the effects of any other specific substitutions of any other nucleotide other than the T at position 568, including any other position within nucleotide positions 562-572 of SEQ ID NO:4. The specification does not specifically define any mutation, i.e. substitution, deletion, or addition, within that particular sequence within SEQ ID NO:4, nor disclose the effects of any such mutations. Likewise, the specification further does not disclose the effects of any deletion or addition, or any combination of substitutions, deletions, and additions in this region of SEQ ID NO:4 or in any other region of SEQ ID NO:4 on the activity of SEQ ID NO:4. In addition, the specification does not disclose any mutations that can be combined with the disclosed substitution at position 568 as set forth in SQ ID NOS 1, 2, and 3 that do not change the activity of these mutant promoter sequences, i.e. the additional mutations result in a promoter with equivalent promoter activity to SEQ ID NOS 1, 2, or 3. Thus, of the large genus of mutant promoter sequences encompassed by the claims, the specification only provides adequate guidance for making and using a mutant synthetic promoter of SEQ ID NO:4 with a single substitution of the T at position 568.
Turning to the state of the art at the time of filing, the prior art teaches that the effects of mutations on promoter sequences cannot be determined a priori, and requires experimental validation. Patwardhan et al., for example, discloses the mutational analysis of one bacteriophage promoter and three different mammalian promoters, including the CMV promoter, and shows that not only did the majority of mutations negatively affect promoter activity, but that the few instances of increased activity due to a single point mutation were not predicted by particular structural elements present in those promoters (Patwardhan et al. (2009) Nat. Biotech., Vol. 27(12), 1173-1175, see Figures 1 and 2). Patwardhan et al. further demonstrates that combining mutations led to unpredictable effects in expression activity of the promoter based on the effects of each mutation separately (Patwardhan et al., Figure 1). In the instant case, the synthetic promoter, as discussed above, combines the enhancer sequence from the CMV promoter, sequence from the chicken beta-actin promoter, and intronic sequence from the TAF1 gene. Patwardhan et al. showed that mutations to the CMV promoter sequence are unpredictable and largely negatively impact activity. The prior art further does not disclose the effects of any or all mutations to the chicken beta promoter. Finally, the preferred site of mutations disclosed by the specification, nucleotides 562-572, is within the intronic sequence, positions 62804-62890, of the human TAF1 gene. The specification is silent as to the activity of this 87 nucleotide intronic sequence, or more specifically the portion of this sequence identified as nucleotides 562-572 of SEQ ID NO:4 . At most, the prior art at the time of filing teaches that intron 32 of the human TAF1 gene is the largest intron, 29,932 bp, in the TAF1 gene, and may possibly include a neuron-specific cis-regulatory element based on the effect of transposon insertion into this intron (Makino et al. (2007) Am. J. Hum. Genet., Vol. 80, 393-406, see pages 403-404). However, neither Makino, nor the prior art as a whole provides any teachings regarding a cis-regulatory element within positions 62804-62890 of the TAF1 gene intron 32, nor do they describe the effects of any mutations in this sequence on the activity of a synthetic promoter which comprises such sequence. Thus, the prior art of record establishes the unpredictability of the effects of introduced mutations on mammalian promoter activity, and is further silent as to any gene regulatory elements present within nucleotides 62804-62890 of the TAF1 gene intron 32, and or its effects, unmutated or mutated, on the activity of a heterologous promoter. Thus, the prior art as a whole establishes the unpredictability in making and identifying a mutant of a promoter which either maintains its promoter activity, or exhibits enhanced promoter activity, particularly where at least one of the mutations is within a sequence present in SEQ ID NO:4 which has unknown properties with regards to promoter or enhancer activity.
As such, based on the unpredictable state of the art at the time of filing for the generation of functional promoter mutants, particularly mutants with increased expression activity, the lack of knowledge in the prior art and the lack of guidance present in the instant specification for the functional properties of the intronic sequence of the TAF1 gene present in SEQ ID NO:4, the lack of guidance present in the specification as to the effects of any mutation to this intronic sequence other than a substitution at position 568 on the promoter function of the synthetic promoter of SEQ ID NO:4, the lack of guidance for the effects of any additional mutations such as substitutions, additions, or deletions to SEQ ID NO:4 on promoter activity, the limitation of the working examples to the activity of the promoters consisting of SEQ ID NOS 1, 2, or 3, and the breadth of the claims, it would have required undue experimentation to make and use claimed products and methods as written.
Additional Comments
It is noted that a synthetic promoter with the sequence of SEQ ID NO:4 was disclosed in an earlier publication by applicant, CN108795946, published in 2018- see SEQ ID NO:3. However, while SEQ ID NO:4 was known in the prior art, neither CN108795946, based on the machine translation available, nor the prior art as a whole, provides teachings to mutate this sequence, or more specifically to mutate this sequence within positions 562-572 of SEQ ID NO:4 to increase the promoter’s expression activity of a heterologous gene in mammalian cells.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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