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 .
DETAILED ACTION
Status of the Application
Claims 1, 2, 4-6, 8-18, 21, 27-31 and 36-38 are pending and are currently under examination.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 36 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 36 recites “A cell” thus encompasses an in vivo cell in a human organism, thereby reading on a human organism.
For examination purpose, the “cell” will be interpreted as an isolated cell.
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.
Claim(s) 6, 29 and 30 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 pre-AIA the applicant regards as the invention.
Claim 6 recites the word "optionally" which renders the claim indefinite because it is unclear if the linker is actually attached to the fusion protein and thus creates ambiguity. See MPEP § 2173.05(h). In the interest of compact prosecution, and given the broadest reasonable interpretation, the word “optionally” will be interpreted as merely indicating an example that is encompassed by the claims but which does not specifically limit the claim to that example.
Claims 29 and 30 recite “a nucleic acid comprising or consisting of a central transposon integration site sequence”. This limitation is unclear because it contains conflicting transitional phrases of ‘comprising’ which is open-ended and does not exclude any other element and contains ‘consisting’ which excludes any element not in the claim. It is therefore unclear if the claim comprises other elements or only consists of a central integration transposon integration site sequence.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Written Description
Claims 1, 2, 4-6, 8-18, 21, 27-31 and 36-38 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” Thus when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The claims are drawn to a genus of one or more linked fusion proteins comprising a DNA targeting domain and a first transpose domain set forth in SEQ ID No. 544 having varying deletions of amino acids 1-103, a TAL domain and at least one mutation selected from the group in claim 10 wherein the fusion protein binds to any nucleic acid or as in claim 5 and being capable of integrating a transgene into a genomic target cell of any cell.
The claims are further drawn to a genus of integration cassettes comprising a nucleic acid comprising or consisting of a central transposon ITR integration site TTAA flanked by one upstream and downstream Zinc Finger Motif DNA.
When determining whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification describes fusion proteins comprising tandem dimer SPB transposase domains with a 20, 40, 60, 100 or 115 amino acid deletions represented as SEQ ID Nos. 9-14 (Example 3). The specification does not describe fusion proteins comprising a DNA targeting domain and a first transpose domain set forth in SEQ ID No. 544 having varying deletions of amino acids 1-103 and the specification does not describe any functional tests to predict what functional domains are needed in polypeptides to still be capable of binding to a target and being capable of integrating a transgene into a genomic target cell. This example does not encompass the vast number of fusion proteins claimed nor the vast number of integration cassettes claimed.
It is then determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristics are targeting integration of ZFM-PBx fusion protein and TAL-Fokl fusions that target specific genes (Example 17). The disclosure has not described the vast number of variable fusion proteins with the function of targeting any gene or integrating a transgene into a genomic target. The disclosure has not described the vast number of integration cassettes comprising a nucleic acid comprising or consisting of a central transposon ITR integration site TTAA flanked by one upstream and downstream Zinc Finger Motif DNA. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant encompassing a vast number of different fusion proteins with varying deleted amino acids and mutations and highly variant integration cassettes, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
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.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must 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 invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every variation of one or more linked fusion proteins comprising a DNA targeting domain and a first transpose domain set forth in SEQ ID No. 544 having varying deletions of amino acids 1-103, a TAL domain and at least one mutation selected from the group in claim 10 or every variation of integration cassettes.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Enablement
Claims 16-18, 21, 27, 28, 37 and 38 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 methods of using a fusion protein such as a Zinc Finger Tandem PBx construct comprising a 10 amino acid deletion that has efficient integration capabilities against two targets (Example 27), a TAL Tandem PBx construct targeting the PAH2 and PAH3 sites as well as Chromosome 17 that has efficient integration capabilities (Example 28-29),
does not reasonably provide enablement for methods of integrating a transgene into any genomic target site of any cell using the claimed genus of fusion proteins or methods of modifying the genome of a cell using the claimed genus of fusion proteins or methods for site-specific transposition of a DNA molecule into the genome using a nucleic acid encoding a fusion protein comprising any DNA binding domain and a transposase.
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 and use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and the nature of the invention:
The broadest reasonable interpretation of the claims in methods of integrating a transgene into a genomic target site and modifying the genome of any cell using a using the genus of one or more linked fusion proteins comprising a DNA targeting domain and a first transpose domain set forth in SEQ ID No. 544 having varying deletions of amino acids 1-103, a TAL domain and at least one mutation selected from the group in claim 10 and methods for site-specific transposition of a DNA molecule into the genome using a nucleic acid encoding a fusion protein comprising any DNA binding domain and a transposase.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
The prior art of Patent No. 9,670,503 (PAT503) teach a fusion protein comprising a piggyBac transposons from Trichoplusia ni (cabbage looper moth) having 99.3% sequence identity to instantly claimed SEQ ID No. 544. A review of the prior art does teach amino acid substitutions and mutations of not provide a correlation between a piggyBac transposons from Trichoplusia ni wherein a fusion protein comprising any of the claimed amino acid substitutions and one or more mutations used in methods of integrating a transgene into any genomic target site of any cell or methods of modifying the genome of a cell.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the prior art does not provide evidence of the degree of predictability for methods of integrating a transgene into any genomic target site of any cell using the claimed genus of fusion proteins or methods of modifying the genome of a cell using the claimed genus of fusion proteins, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The existence of working examples:
The working embodiment in the instant application describes a fusion protein such as a Zinc Finger Tandem PBx construct comprising a 10 amino acid deletion as having efficient integration capabilities against two targets (Example 27), a TAL Tandem PBx construct targeting the PAH2 and PAH3 sites as well as Chromosome 17 has efficient integration capabilities (Example 28-29). The working embodiments do not describe the claimed methods encompassing the vast number of fusion proteins and integration cassettes.
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests methods of integrating a transgene into any genomic target site of any cell using the claimed genus of fusion proteins or methods of modifying the genome of a cell using the claimed genus of fusion proteins or methods for site-specific transposition of a DNA molecule into the genome using a nucleic acid encoding a fusion protein comprising any DNA binding domain and a transposase.
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the role any fusion protein as claimed plays in binding to any sequence and integrating a transgene into a genomic target. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
Closest Prior Art
The closest prior art is Patent No. 9,670,503 (PAT503) that teach a fusion protein comprising a piggyBac transposons from Trichoplusia ni (cabbage looper moth) having 99.3% sequence identity to instantly claimed SEQ ID No. 544. PAT503 does not teach a fusion protein comprising a transposase domain having deletions of amino acids 1-103 of SEQ ID No. 544 and wherein the transposase domain has mutations as in claim 10.
SEQ ID NO 57
LENGTH: 594
ORGANISM: Trichoplusia ni
Query Match 99.3%; Score 3107; Length 594;
Best Local Similarity 99.5%;
Matches 590; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 2 GSSLDDEHILSALLQSDDELVGEDSDSEVSDHVSEDDVQSDTEEAFIDEVHEVQPTSSGS 61
Db 2 GSSLDDEHILSALLQSDDELVGEDSDSEVSDHVSEDDVQSDTEEAFIDEVHEVQPTSSGS 61
Qy 62 EILDEQNVIEQPGSSLASNRILTLPQRTIRGKNKHCWSTSKSTRRSRVSALNIVRSQRGP 121
Db 62 EILDEQNVIEQPGSSLASNRILTLPQRTIRGKNKHCWSTSKSTRRSRVSALNIVRSQRGP 121
Qy 122 TRMCRNIYDPLLCFKLFFTDEIISEIVKWTNAEISLKRRESMTSATFRDTNEDEIYAFFG 181
Db 122 TRMCRNIYDPLLCFKLFFTDEIISEIVKWTNAEISLKRRESMTSATFRDTNEDEIYAFFG 181
Qy 182 ILVMTAVRKDNHMSTDDLFDRSLSMVYVSVMSRDRFDFLIRCLRMDDKSIRPTLRENDVF 241
Db 182 ILVMTAVRKDNHMSTDDLFDRSLSMVYVSVMSRDRFDFLIRCLRMDDKSIRPTLRENDVF 241
Qy 242 TPVRKIWDLFIHQCIQNYTPGAHLTIDEQLLGFRGRCPFRVYIPNKPSKYGIKILMMCDS 301
Db 242 TPVRKIWDLFIHQCIQNYTPGAHLTIDEQLLGFRGRCPFRVYIPNKPSKYGIKILMMCDS 301
Qy 302 GTKYMINGMPYLGRGTQTNGVPLGEYYVKELSKPVHGSCRNITCDNWFTSIPLAKNLLQE 361
Db 302 GTKYMINGMPYLGRGTQTNGVPLGEYYVKELSKPVHGSCRNITCDNWFTSIPLAKNLLQE 361
Qy 362 PYKLTIVGTVASNAREIPEVLKNSRSRPVGTSMFCFDGPLTLVSYKPKPAKMVYLLSSCD 421
Db 362 PYKLTIVGTVRSNKREIPEVLKNSRSRPVGTSMFCFDGPLTLVSYKPKPAKMVYLLSSCD 421
Qy 422 EDASINESTGKPQMVMYYNQTKGGVDTLNQMCSVMTCSRKTNRWPMALLYGMINIACINS481
Db 422 EDASINESTGKPQMVMYYNQTKGGVDTLDQMCSVMTCSRKTNRWPMALLYGMINIACINS481
Qy 482 FIIYSHNVSSKGEKVQSRKKFMRNLYMSLTSSFMRKRLEAPTLKRYLRDNISNILPKEVP 541
Db 482 FIIYSHNVSSKGEKVQSRKKFMRNLYMSLTSSFMRKRLEAPTLKRYLRDNISNILPKEVP 541
Qy 542 GTSDDSTEEPVMKKRTYCTYCPSKIRRKANASCKKCKKVICREHNIDMCQSCF 594
Db 542 GTSDDSTEEPVMKKRTYCTYCPSKIRRKANASCKKCKKVICREHNIDMCQSCF 594
At the time of filing, Zhao et al. ("PiggyBac transposon vectors: the tools of the human gene encoding." Translational lung cancer research 5.1 (2016): 120) teach DNA segments of transposons that can recognize transposon-specific inverted terminal repeats (ITRs) sequences located on both ends of the transposon vector and eight efficiently moves the contents from its original positions and efficiently integrates them into TTAA chromosomal sites (see abstract and page 122). Zhao et al. does not teach or make obvious to claimed fusion protein comprising a transposon or an integration cassette as claimed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
Prosecution Insights