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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a provisional application filed as 63/252,030 on 10/04/2021.
All claims are given the priority date of 10/04/2021.
Application Status
Receipt is acknowledged of amendment, filed 10/28/2024. Claims 1-21 are currently pending.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statement filed on 07/23/2024 has been received and all references have been considered.
Specification
The use of the terms piggyBac and Super piggyBac, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 13 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 13 recites “a cell comprising the polynucleotide of claim 1”. While claims immediately considered on merits recite a composition, the specification describes methods of treating a subject where the transposon composition will be administered for treating or preventing a disorder [041; 081; 0279; 0347 and 0358]. Furthermore, instant withdrawn claims 20 and 21 recite a method of treatment. Accordingly, when the claimed transposon composition is delivered to a human cell, the cells of the human subject will comprise the transposon composition claimed. Therefore, the claims would encompass cells in a human organism and the human organism itself.
Amending the claim to an isolated cell or a cell in vitro will be remedial.
Claim 19 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 19 recites “A composition comprising the population of modified cells produced according to the method of claim 15”. While claims immediately considered on merits recite a composition, the specification describes methods of treating a subject where the transposon composition will be administered for treating or preventing a disorder [041; 081; 0279; 0347 and 0358]. Furthermore, instant withdrawn claims 20 and 21 recite a method of treatment. Accordingly, when the claimed transposon composition is delivered to a human cell or a plurality of human cells, the cells of the human subject will comprise the transposon composition claimed. Therefore, the claims would encompass cells in a human organism and the human organism itself.
Amending the claim to an isolated cell or a cell in vitro will be remedial.
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 6, 7, 16 and 17 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.
Claims 6, 7 and 16 contain the trademark/trade name “piggyBac”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a mobile genetic element that moves DNA between vectors and chromosomes using the “cut-and-paste” mechanism and, accordingly, the identification/description is indefinite.
Claim 17 contains the trademark/trade name “Super piggyBac™ (SPB)”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an engineered and highly active mobile genetic element that moves DNA between vectors and chromosomes using the “cut-and-paste” mechanism and, accordingly, the identification/description is indefinite.
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 1-21 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.
Claims 1-21 are drawn to a genus of transposon comprising a first inverted terminal repeat and second inverted terminal repeat. The rejected claims thus comprise a genus of first inverted terminal repeats that encompass at least 99% identity to SEQ ID NO: 4 but also must have at least one nucleic acid substitution at position 31 or 33.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes while many mutants showed improvement over wildtype excision and integration, mutant transposons with a 31 TCC mutation on the LE LTR (i.e. substitutions 31 G>T and 33A>C) showed the highest increase of cells with of excision and/or integration [037]. The specification describes that overall, 1 bp substitutions were well tolerated; however, a difference of enrichment was observed in the 5' and 3' ends, showing mutations have more extreme effects in the 5' and 3' ITR regions than the internal "ITR-like" region and mutations within the 13bp repeat region have a stronger effect than mutations within the l9bp repeat region [0483]. The specification describes the use of the 31TCC mutation of the LE ITR (SEQ ID NO: 16) (i.e. substitutions 31G>T and 33A>C) resulted in the highest percentage of cells with transposition activity (i.e. excision and/or integration) [0495]. No description is provided of a first inverted terminal repeat that has a substitution at nucleic acid position 31 and/or 33 and at least 99% identity to instant SEQ ID NO: 4. Specifically, both substitutions made at nucleic acid positions 31 and 33 in SEQ ID NO: 4 resulted in SEQ ID NO: 16 which showed to be only 90.9% identical to the sequence of SEQ ID NO: 4 over its entire length (See Appendix I). In addition, even when only one substitution, 31G>T or 33A>C, was performed on the sequence of SEQ ID NO: 4, it resulted in 95.4% sequence identity to instant SEQ ID NO: 4 (See Appendix II and III, respectively). Therefore, any of the substitutions, either single or both, would result in less than 99% identity to instant SEQ ID NO: 4.
None of the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the use of SEQ ID NO: 16 which is the sequence of SEQ ID NO: 4 with both substitutions made at nucleic acid positions 31 and 33, however, SEQ ID NO: 16 is only 90.9% identical to the sequence of SEQ ID NO: 4 over its entire length (See Appendix I). In addition, even when only one substitution, 31G>T or 33A>C, was performed on the sequence of SEQ ID NO: 4, it resulted in 95.4% sequence identity to instant SEQ ID NO: 4 (See Appendix II and III, respectively). Therefore, any of the substitutions, wither single or both, would result in less than 99% identity to instant SEQ ID NO: 4. The results are not necessarily predictive of first inverted terminal repeats that would be 99% identical to SEQ ID NO: 4 as well as having a substitution at either one or both of nucleic acid positions 31 and 33. Thus, it is impossible for one to extrapolate from the few examples described herein those first inverted terminal repeats that would be 99% identical to SEQ ID NO: 4 as well as having a substitution at either one or both of nucleic acid positions 31 and 33 that would necessarily meet the structural/functional characteristics of the rejected claims.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-21.
Claims 1-21 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The claims are drawn to a polynucleotide encoding a transposon comprising: a) a first inverted terminal repeat (ITR) comprising a nucleic acid sequence having at least 99% identity to SEQ ID NO: 4 comprising a nucleic acid substitution in at least one of nucleic acid position 31 and 33; and b) a second ITR comprising a nucleic acid sequence having at least 99% identity to SEQ ID NO: 5. The nature of the invention is complex in that it is not possible for the sequence of SEQ ID NO: 4 to have either one or both of the substitutions at positions 31 and 33 and still retain 99% identity compared to SEQ ID NO: 4. Dependent claims 2-5 all require substitutions that would result in less than 99% identity to SEQ ID NO: 4 which is required by independent claim 1. Therefore, claims 2-5 are broader than independent claim 1 from which they depend.
Furthermore, dependent claims 20 and 21 provide method steps for treatment of a disease or disorder by administration of the product of independent claim 1 for the treatment of cancer, a liver disease or disorder, a urea cycle disorder, a metabolic liver disorder or a hemophilia disease. The nature of the invention is complex in that the administration of the transposon alone to a subject would not result in any therapeutic or treatment of any disease or disorder.
Breadth of the claims: The claims specifically require the first inverted terminal repeat (ITR) to comprise a nucleic acid sequence having at least 99% identity to SEQ ID NO: 4 while comprising a nucleic acid substitution in at least one of nucleic acid position 31 and 33.
Claims 20 and 21 are broadly drawn to the treatment of any disease or disorder by administration of only the transposon with a modified first ITR for the treatment of cancer, a liver disease or disorder, a urea cycle disorder, a metabolic liver disorder or a hemophilia disease. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification teaches while many mutants showed improvement over wildtype excision and integration, mutant transposons with a 31 TCC mutation on the LE LTR (i.e. substitutions 31 G>T and 33A>C) showed the highest increase of cells with of excision and/or integration [037]. The specification teaches that overall, 1 bp substitutions were well tolerated; however, a difference of enrichment was observed in the 5' and 3' ends, showing mutations have more extreme effects in the 5' and 3' ITR regions than the internal "ITR-like" region and mutations within the 13bp repeat region have a stronger effect than mutations within the l9bp repeat region [0483]. The specification teaches the use of the 31TCC mutation of the LE ITR (SEQ ID NO: 16) (i.e. substitutions 31G>T and 33A>C) resulted in the highest percentage of cells with transposition activity (i.e. excision and/or integration) [0495]. No description is provided of a first inverted terminal repeat that has a substitution at nucleic acid position 31 and/or 33 and at least 99% identity to instant SEQ ID NO: 4. Specifically, both substitutions made at nucleic acid positions 31 and 33 in SEQ ID NO: 4 resulted in SEQ ID NO: 16 which showed to be only 90.9% identical to the sequence of SEQ ID NO: 4 over its entire length (See Appendix I). In addition, even when only one substitution, 31G>T or 33A>C, was performed on the sequence of SEQ ID NO: 4, it resulted in 95.4% sequence identity to instant SEQ ID NO: 4 (See Appendix II and III, respectively). Therefore, any of the substitutions, either single or both, would result in less than 99% identity to instant SEQ ID NO: 4.
In addition, the specification envisions the use of a disclosed composition or pharmaceutical composition for the treatment of a disease or disorder in a cell, tissue, organ, animal, or subject, as known in the art or as described herein, using the disclosed compositions and pharmaceutical compositions, e.g., administering or contacting the cell, tissue, organ, animal, or subject with a therapeutic effective amount of the composition or pharmaceutical composition [0358]. The working examples of the instant specification envision screening the mutant LE ITRs within HEK 293T cells, K562 cells and primary T cells [0493-0497]. However, no description is provided of how delivering only a transposon with a modified first ITR to a cell would result in the treatment of a disease or disorder, specifically treatment of cancer, a liver disease or disorder, a urea cycle disorder, a metabolic liver disorder or a hemophilia disease.
Predictability and state of the art: For some relevant background, Tipanee et al (Hum Gene Ther. 2017 Nov;28(11):1087-1104) teaches stable transposition requires co-delivery of the transposon DNA with the corresponding transposase gene, mRNA, or protein (Page 1087, Abstract). Tipanee teaches the therapeutic potential of these SB- and PB-based transposons has been demonstrated in preclinical models that mimic the cognate human diseases; however, there are still challenges impeding clinical translation of transposons pertaining mainly to the typical limiting efficiencies of most non-viral transfection methods and the intrinsic DNA toxicity (Page 1087, Abstract). Tipanee teaches the main advantage is that all of the functional domains were retained in contrast to when truncated dystrophins were employed, but the overall efficiency was reduced due to the intrinsic DNA toxicity after electroporation (Page 1093, Column 2). Tipanee teaches that despite their promise, delivery remains a challenge requiring the use of non-viral transfection methods that often result in significant cytotoxicity, specifically, the overall efficacy of non-viral in vivo transfection is often limited and/or the transfection methods used are not readily amenable for clinical applications (e.g., hydrodynamic transfection) (Page 1099, Column 2).
In addition, Kumar et al (F1000Res. 2020 Feb 24;9: F1000 Faculty Rev-135; Pgs. 1-12) teaches the impact of transposition is profound, as over 100 human heritable diseases have been attributed to transposon insertions (Page 1, Abstract). Kumar teaches the impact of transposition on gene expression and function at insertion loci is substantial, and the disease implications of transposons as hotspots for mutation are still being understood, therefore very unpredictable (Page 8, Column 2).
Amount of experimentation necessary: In order to practice the claimed invention, an immense amount of experimentation would be required. As disclosed above, the specification itself provides administration of a pharmaceutical composition comprising the transposon with the modified first ITR to a cell, tissue, organ, animal or subject for the treatment of a disease or disorder, specifically the treatment of cancer, a liver disease or disorder, a urea cycle disorder, a metabolic liver disorder or a hemophilia disease. However, no description is provided of what purpose or if it is safe to deliver only a transposon with a modified first ITR to a cell, tissue, organ, animal or subject for the treatment of a disease or disorder. Additionally, the specification itself provides description of the use of the 31TCC mutation of the LE ITR (SEQ ID NO: 16) (i.e. substitutions 31G>T and 33A>C) that resulted in the highest percentage of cells with transposition activity (i.e. excision and/or integration) [0495]. No description is provided of a first inverted terminal repeat that has a substitution at nucleic acid position 31 and/or 33 and at least 99% identity to instant SEQ ID NO: 4. Specifically, both substitutions made at nucleic acid positions 31 and 33 in SEQ ID NO: 4 resulted in SEQ ID NO: 16 which showed to be only 90.9% identical to the sequence of SEQ ID NO: 4 over its entire length (See Appendix I). In addition, even when only one substitution, 31G>T or 33A>C, was performed on the sequence of SEQ ID NO: 4, it resulted in 95.4% sequence identity to instant SEQ ID NO: 4 (See Appendix II and III, respectively). Therefore, any of the substitutions, wither single or both, would result in less than 99% identity to instant SEQ ID NO: 4. Except for the full sequences disclosed and claimed as instant SEQ ID NO: 16, for experimentation, first the substitutions to improve efficiency of the transposase activity within a cell would need to be identified wherein this would require a large amount of experimentation with no knowledge of which structures would be capable of performing the function of inhibition prior to screening. Second, the transposon having the first inverted terminal repeat of instant SEQ ID NO: 16 would need to be tested in order to confirm that the substitutions of the first ITR would be capable of successfully increases the transposase activity within a cell. Finally, the transposons comprising substitutions of the first ITR would need to be tested in an art-accepted model in order to identify if the modified transposons are successfully capable of accomplishing transposase activity within a cell. The specification does teach that the use of the 31TCC mutation of the LE ITR (SEQ ID NO: 16) (i.e. substitutions 31G>T and 33A>C) resulted in the highest percentage of cells with transposition activity (i.e. excision and/or integration) [0495]. Therefore, experiment could be conducted, but in view of the specification there does not appear to be any amount of experimentation that would be sufficient to reliably produce the exact product of the invention. Therefore, it would require immense amount of unpredictable experimentation to practice the claimed invention with such variants in the possible result.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-21 are not considered to be fully enabled by the instant disclosure.
Conclusion
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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