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 .
Claim status
There is a typo for claims 39-50 on pg 5 of the response filed 4-13-26. It should say ---39-50---, not “9-50”.
Claims 1, 4-9, 12-15, 17-21, 23-28, 31, 33-37, 39-50, 55, 58-60, 62, 66-68, 70-73, 75-81 have been canceled. Claims 2, 3, 10, 11, 16, 22, 29, 30, 32, 38, 51-54, 56, 57, 61, 63-65, 69, 74 are pending.
Applicant's arguments filed 4-13-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim objection
The abbreviation ZFHD1 in claim 10 should be spelled out before being abbreviated.
The structure of the coding sequences, the fusion transcription factor protein, and the operable linkage of the sequences encoding the fusion transcription factor and the DRD in claim 10 can be written more concisely and accurately. The two species of DRD can be set forth more clearly up front. The two domains of the fusion transcription factor can be set forth more clearly up front. E.g. ---[An isolated genetically modified mammalian] cell comprising a nucleic acid sequence encoding a carbonic anhydrase 2 (CA2) or dihydrofolate reductase (DHFR) drug responsive domain (DRD) operably linked to a nucleic acid sequence encoding a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain, wherein…---.
If the nucleic acids encode a fusion protein comprising i) the fusion transcription factor and ii) the DRD, then much clarification will be required, e.g. ---[An isolated genetically modified mammalian] cell comprising a nucleic acid sequence encoding a fusion protein comprising i) a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain operably linked to ii) a carbonic anhydrase 2 (CA2) drug responsive domain (DRD) or dihydrofolate reductase (DHFR) DRD---.
The “wherein…” function of the fusion transcription factor in claim 10 cannot be determined at this time. It is unclear whether the 3rd nucleic acid encoding a protein of interest is in the cell or not. If the 3rd nucleic acid is not in the cell, then the function/relationship of the 3rd nucleic acid to the sequence encoding the fusion transcription factor operably linked to the sequence encoding the DRD in the cell cannot be determined. It is unclear whether the “specific polynucleotide binding site” is in the cell or not. The phrase “polynucleotide binding site” in claim 10 is problematic because it infers a “binding site” for binding polynucleotides, but it appears to be a ---transcription factor binding site---, i.e. a polynucleotide site that binds to a transcription factor. The function/relationship of the “specific polynucleotide binding site” to the sequence encoding the nucleic acid encoding the protein of interest and the sequence encoding the fusion transcription factor operably linked to the sequence encoding the DRD in the cell cannot be determined. Perhaps the 3rd nucleic acid is a ---nucleic acid sequence encoding a protein of interest operably linked to a transcription factor binding site---. But if it is not in the cell, then it is unclear how the concept further limits the function of the cells or the polynucleotide in the cell.
Claim 11 can be written more clearly as ---wherein the nucleic acid sequence encoding the protein of interest is operably linked to a transcription factor binding site and an inducible promoter---.
Election/Restrictions
Applicants elected Group II, claims 10, 11, 15, 16, 22, 79, 80, without traverse in the reply filed on 7-6-22.
Claims 2, 3, 29, 30, 32, 38, 51-54, 56, 57, 61, 63-65, 69, 74 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9-29-25.
Claims 10, 11, 16, 22 remain under consideration.
Further restriction may be required upon clarifying the structures/functions encompassed by claim 10 based on the type of “transcription factor”, the [non-existent] ligand, binding site, and protein of interest. In particular, if the invention relies upon a fusion protein comprising a destabilizing domain and a transcription factor, then restriction may be required based on each type of transcription factor, e.g. c-Jun, Foxp3, ZFHD1, Cas9, Cas12, and TAL in claim 79. If the invention relies upon a transcription factor for regulating expression of a protein of interest, then restriction may be required based on the type of protein of interest.
Specification
The title will have to be changed to more closely reflect the claimed subject matter. In particular, it is unclear when regulation of transcription is “tunable”.
Claim Rejections - 35 USC § 112
Written Description
Claims 10, 11, 15, 16, 22, 79, 80 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 and scope
Claim 10 is drawn to a “modified cell comprising a polynucleotide comprising a first nucleic acid sequence encoding a drug responsive domain (DRD) and a second nucleic acid sequence encoding a transcription factor, wherein the transcription factor comprises a transcription factor DNA binding domain derived from ZFHD1 and a transcription factor activation domain derived from p65, wherein the transcription factor is operably linked to the DRD, wherein the DRD is derived from carbonic anhydrase 2 (CA2) or human dihydrofolate reductase (hDHFR); and wherein the transcription factor is able to bind to a specific polynucleotide binding site and activate transcription of a third nucleic acid sequence encoding a protein of interest, wherein the third nucleic acid sequence is operably linked to the specific polynucleotide binding site.”.
The claim encompasses any species of cell including bacteria, plant, invertebrate, insect, fish, amphibian, reptile, bird, or mammalian cells. The claim encompasses cells in vivo or in vitro.
The metes and bounds of a carbonic anhydrase 2 (CA2) drug responsive domain (DRD) or dihydrofolate reductase (DHFR) DRD in claim 10 cannot be determined (see also 112/2nd rejection). The specification uses the term or the abbreviation of DRD multiple times from pg 1-65 without defining the metes and bounds. Para 153-155 on pg 65-66 discusses DRDs without defining them. Para 153 says they are “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” and is “interchangeable with the term destabilizing domain (DD)”. The paragraph goes on to say DRDs can be applied to proteins to make them unstable. Para 154 says DRDs may be derived from known proteins. However, this discussion is so scientifically confusing and vague as to be meaningless. An antigen may bind an antibody, but it is unclear how the antigen is “unstable and degraded” in the absence of a ligand. A portion of a protein may be antigenic and capable of binding an antibody, but it is unclear how the antigenic portion is “unstable and degraded” in the absence of a ligand. It is unclear what “well-known” proteins DRDs are ”derived from”. Para 155 says the “parent protein” may be FKBP, DHFR, PDE5, CA2, or estrogen receptor for example (pg 66); however, it is unclear how to derive any DRDs from FKBP, DHFR, PDE5, CA2, or estrogen receptor. It is also unclear how to test any peptide derived from FKBP, DHFR, PDE5, CA2, estrogen receptor, or any other protein to determine whether it “unstable and degraded in the absence of a ligand” “but whose stability is rescued by binding to a corresponding DRD-binding ligand”. The specification and the art at the time of filing do not teach when a fragment of FKBP, DHFR, PDE5, CA2, estrogen receptor, or any other protein is “unstable” in the absence of a ligand. The specification does not teach any fragments of FKBP, DHFR, PDE5, CA2, estrogen receptor, or any other protein that degrade in the absence of a ligand. Table 3 - pg 67-68 – shows “Proteins and their ligand”; however, these proteins may bind other ligands called antibodies. It is unclear why the proteins listed in table 3 would be unstable or degrade upon binding an antibody. It is also unclear if the proteins listed in Table 3 ARE the DRDs or if DRDs are derived from the proteins listed in Table 3. If DRDs are derived from the proteins listed in Table 3, then it is unclear how to do so or how to assay whether they degrade or are unstable when bound to an antibody or their corresponding ligand listed in Table 3. Pg 68-81 discuss FKBP, DHFR, PDE5, CA2, or estrogen receptor DRDs in more detail without defining the metes and bounds of the phrase. Accordingly, the metes and bounds of a CA2 DRD or DHFR DRD in claim 10 cannot be determined.
Lines 1-7 of claim 10 require a nucleic acid sequence encoding a DRD and a sequence encoding what appears to be a fusion “transcription factor”, “wherein the transcription factor is operably linked to the DRD”. This does not make scientific, logical, or legal sense because there is no expression of the “transcription factor” or the DRD and because it is unclear if the “transcription factor” bound to the DRD is the ligand that makes the DRD stable (according to paragraph 153) or if it is some other entity.
Lines 8-10 of claim 10 require the transcription factor is able to bind a “specific polynucleotide binding site” and activate transcription of a third sequence encoding a protein of interest operably linked to the “specific polynucleotide binding site”. The metes and bounds of when a nucleic acid sequence is “specific” cannot be determined. Perhaps applicants are simply trying to say the transcription factor is capable of binding to a polynucleotide and activating transcription or a protein of interest at that binding site; however, “specific” makes the phrase unclear. The concept can be written much more simply if it’s just a matter of the transcription factor having a capability of transcribing a protein of interest. If the third sequence is part of the genetic modification in the cell, however, much clarification is required.
Overall, the metes and bounds of the structure and function of the modification in claim 10 cannot be determined.
Art at the time of filing
Zhang (WO 2016106244) taught a cell comprising a nucleic acid sequence encoding Cas9 operably linked to a nucleic acid sequence encoding a destabilizing domain (DD) capable of expressing a fusion protein comprising Cas9 and the DD, wherein the fusion protein is capable of binding a specific target site and inducing expression of a protein of interest (para 13, 48). The DD may be derived from DHFR; the ligand may be TMP (para 13). Cas9 may have transcription activators, e.g. VP64 of p65, attached (para 48). This is appear to be within the metes and bounds of claim 10, but claim 10 does not represent the elements accurately or have all the elements required for successful control of expression of a protein of interest.
Teachings in the specification and examples
Fig. 1A is limited to a DRD comprising a DNA binding domain (DBD), a transcription factor activation domain (TAD), and a drug responsive domain (DRD). This is completely missing from claim 10 and fails to explain the metes and bounds of what applicants consider a DRD. It is unclear whether claim 10 encompasses the DBD or TAD in Fig. 1A.
Fig. 1B discusses a “payload construct” with a DBD binding site, a minimal promoter, and a “payload”; however, it is unclear whether claim 10 encompasses any of these concepts.
Pg 89-92 discuss ligands for FKBP, DHFR, PDE5, CA2, or estrogen receptor.
Pg 92-101 discuss various “payloads” but it is unclear how they correlate to the elements of claim 10.
Pg 103-115 discusses delivering nucleic acids to cells.
Pg 118-142 discusses therapeutic uses, but it is unclear how the cell of claim 10 is therapeutic. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for therapeutic purposes. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for therapeutic purposes.
Pg 142-144 discusses “gene editing” uses, but it is unclear how the cell of claim 10 is used for “gene editing”. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for “gene editing” purposes. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for “gene editing” purposes.
Pg 144-152 discuss “other uses”, but it is unclear how the cell of claim 10 is used for “gene editing”. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for “other uses”. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for “other uses”.
Definitions are on pg 152-179. No definition of DRDs can be found in this section.
Example 1 (pg 179) discusses the design of transcription factor systems and is limited to the structure in Fig. 1A and 1B:
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It is unclear from the discussion in Example 1 how to use the system, how to regulate expression of the “payload”, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 1 how to regulate or control expression of the “payload”. It is unclear from the discussion in Example 1 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 1 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 1 correlate to the elements in claim 10 and which elements in Example 1 are missing from claim 10. In fact, it is unclear what elements in Example 1 are required to obtain any desired functionality or regulation of expression. It is unclear whether the system is inducible or not. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload.
Example 2 (pg 183) discusses viral production and cell line generation. It is unclear from the discussion in Example 2 how to use the system, how to regulate expression of the “payload”, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 2 how to regulate or control expression of the “payload”. It is unclear from the discussion in Example 2 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 2 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 2 correlate to the elements in claim 10 and which elements in Example 2 are missing from claim 10. In fact, it is unclear what elements in Example 2 are required to obtain any desired functionality or regulation of expression. It is unclear whether the system is inducible or not. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload.
Example 3 (pg 184) discusses ligand-dependent regulation of transcription factors, but claim 10 does not require any ligand or that the DRD is expressed or that the DRD is controlled by any ligand. It is unclear from the discussion in Example 3 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 3 how to regulate or control expression of the “payload” using a ligand. It is unclear from the discussion in Example 3 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 3 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 3 correlate to the elements in claim 10 and which elements in Example 3 are missing from claim 10. In fact, it is unclear what elements in Example 3 are required to obtain any desired functionality or regulation of expression using any ligand. It is unclear whether the system is inducible or not. If so, it is unclear whether the ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload. However, the discussion in Example 3 is limited to using specific ligands that bind specific DRDs, but claim 10 makes no reference to any ligand.
Example 4 (pg 186) and 5 (pg 188) and 6 (pg 189) an 11 (pg 194) are specific for a ecDHRF DRD-regulated transcription factor system, but claim 10 does not require any ligand, specifically ecDHRF, or that the DRD is expressed or that the DRD is controlled by any ligand, specifically ecDHRF. It is unclear from the discussion in Example 4-6, 11 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 4-6, 11 how to regulate or control expression of the “payload” using a ligand, specifically ecDHRF. It is unclear from the discussion in Example 4-6, 11 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 4-6, 11 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 4-6, 11 correlate to the elements in claim 10 and which elements in Example 4-6, 11 are missing from claim 10. In fact, it is unclear what elements in Example 4-6, 11 are required to obtain any desired functionality or regulation of expression using any ligand, specifically ecDHRF. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand, specifically ecDHRF, is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of any “payload. The discussion in Example 4-6, 11 is limited to using a specific ligand, ecDHRF, which binds to specific DRDs, but claim 10 makes no reference to any ligand.
Example 7 (pg 190) and 8 (pg 192) and 9 (pg 192) and 10 (pg 193) and 12 (pg 195) and 14 (pg 198) are specific for a CA2 DRD-regulated transcription factor system, but claim 10 does not require any ligand, specifically ecDHRF, or that the DRD is expressed or that the DRD is controlled by any ligand, specifically ecDHRF. It is unclear from the discussion in Example 7-9, 11, 12 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 7-9, 11, 12 how to regulate or control expression of the “payload” using a ligand, specifically ecDHRF. It is unclear from the discussion in Example 7-9, 11, 12 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 7-9, 11, 12 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 7-9, 11, 12 correlate to the elements in claim 10 and which elements in Example 7-9, 11, 12 are missing from claim 10. In fact, it is unclear what elements in Example 7-9, 11, 12 are required to obtain any desired functionality or regulation of expression using any ligand, specifically ecDHRF. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand, specifically ecDHRF, is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of any “payload. The discussion in Example 7-9, 11, 12 is limited to using a specific ligand, ecDHRF, which binds to specific DRDs, but claim 10 makes no reference to any ligand.
Example 16 (pg 200) discusses expressing IL-12 as the payload. However, the example is limited to using constructs ZFHD-005 (example 4) and ZFHD-13 which encodes IL-12. “Ligand treatment” is discussed on pg 200, para 703, but claim 10 does not require any ligand, that the DRD is expressed, or that the DRD is controlled by any ligand. It is unclear from the discussion in Example 16 how to use the system, how to regulate expression of the IL12 “payload” using a ligand, or how the IL12 “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 16 how to regulate or control expression of the IL12 “payload” using a ligand. It is unclear from the discussion in Example 16 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 16 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 16 correlate to the elements in claim 10 and which elements in Example 16 are missing from claim 10. In fact, it is unclear what elements in Example 16 are required to obtain any desired functionality, expression of the IL12 “payload”, or regulate expression of an IL12 “payload” using any ligand. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing IL12 expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of an IL12 “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of an IL12 “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of an IL12 “payload. The discussion in Example 16 does not teach the specific ligand that binds to the specific DRD, and claim 10 makes no reference to any ligand.
Example 17 (pg 201) discusses ligand-dependent regulation of FOXP3 transcription factors. Example 17 (pg 201) and 18 (pg 203) discuss ligand-dependent regulation of c-Jun transcription factors. Examples 17 and 18 are deficient for reasons set forth above.
Claim 10 encompasses using a sequence encoding an ecDHFR or CA2 DRD having the amino acid sequence of SEQ ID NO: 1 in Table 3 on pg 66 (or perhaps applicants are saying a DRD is a peptide “derived” from SEQ ID NO: 1 or 5) in combination with a sequence encoding any transcription factor that binds any binding site operably linked to a sequence encoding any protein of interest. However, claim 10 is missing any functional link between the elements that involve the ligand that is specific to the CA2 or DHFR DRD, and the specific transcription factor and specific binding site that induce expression of the protein of interest. None of the claims are limited to any specific CA2 or DHFR DRD, any specific ligand, or any specific binding site that would induce expression of a protein of interest. There are no teachings in the specification about how to operably link CA2 or DHFR DRD with a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain. There are no teachings in the specification about how to use a fusion protein comprising i) CA2 or DHFR DRD operably linked to ii) a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain.
Accordingly, the specification lacks written description for any [1st] nucleic acid sequence encoding a CA2 or DHFR DRD operably linked to a [2nd] sequence encoding a fusion transcription factor comprising a ZFHDA DNA binding domain and a p65 activation domain that binds a [3rd] sequence encoding a protein of interest operably linked to a [transcription factor] binding site as required in claim 10.
The specification lacks written description for making any species of cell in vitro or in vivo as broadly encompassed by claim 10 other than isolated mammalian cells. The specification does not teach or suggest doing so in invertebrate, insect, amphibian, reptile, or bird cells. The specification does not contemplate constructing the cells in vivo. Therefore, the claims should be limited to isolated mammalian cells.
The specification lacks written description for a nucleic acid encoding a protein of interest operably linked to an inducible promoter as required in claim 11. Looking to example 16 (pg 200) as the most specific example of a 3rd nucleic acid sequence encoding a protein of interest, there is no inducible promoter in the Example or in the ZFHD-005 or -013 constructs used to make the cells, and there is no inducer added to the cells that causes IL12 expression. Pg 201, para 703, is limited to “ligand treatment” which does not appear to allow expression of IL12, so the “ligand” for whatever DRD is in Example 16 does not involve an “inducible promoter” as required in claim 11. Therefore, the concept in claim 11 lacks written description.
The specification lacks written description for any DRD “derived” from CA2 or DHFR as required in claim 10 for reasons set forth above. The specification lacks written description for using any specific DRD “derived” from CA2 or DHFR in combination with any ZFHD1/p65 fusion transcription factor, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
The specification lacks written description for any CA2 or DHRF DRD “stabilized in the presence of” ACZ, MTX, or TMP as required in claim 16 for reasons set forth above. The specification lacks written description for using any CA2 or DHRF DRD “stabilized in the presence of” ACZ, MTX, or TMP in combination with any ZFHD1/p65 fusion transcription factor, any binding site, and any ligand as broadly encompassed by claim 16 for reasons set forth above.
The specification lacks written description for any transcription factor comprising a ZFHD1 DNA binding domain as required in claim 10. While ZFHD1 is a transcription factor and has a DNA binding domain, it is unclear when a DNA binding domain is “derived from” ZFHD1 as claimed. The specification lacks written description for using any “DNA binding domain” “derived from” ZFHD1 other than a ZFHD1 DNA binding domain. The specification lacks written description for using a ZFHD1 DNA binding domain in combination with any CA2 or DHFR DRD, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
The specification lacks written description for any transcription factor activation domain that is “derived from” p65 as required in claim 10. While p65 is a transcription factor and has an “activation domain”, it is unclear when an activation domain is “derived from” p65 as claimed. The specification lacks written description for using any “activation domain” “derived from” p65 other than a p65 activation domain. the specification lacks written description for using any p65 activation domain in combination with any CA2 or DHRF DRD, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Applicants point to case law. Applicants’ argument is not persuasive because the fact patterns in this case are not the same as those cases.
Applicants point to Examples 2, 3, 7, 10 which teach a fusion transcription factor comprising a DNA binding domain “derived from” ZFHD1 and an activation domain “derived from” p65. Applicants’ argument is not persuasive because the examples are limited to a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain. The phrase “derived from” encompasses anything that resembles and shares any structure or function of a ZFHD1 DNA binding domain or p65 activation domain. But applicants simply used a ZFHD1 DNA binding domain and p65 activation domain without any further “derivations”.
If applicants are attempting to say Examples 2, 3, 7, 10 taught a nucleic acid sequence encoding a fusion protein comprising i) a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain operably linked to ii) a CA2 DRD or DHFR DRD, then please point to such a coding sequence/fusion protein specifically. Please also teach the function of the fusion protein, especially as it relates to the “nucleic acid sequence encoding a protein of interest” operably linked to a “specific [transcription factor] binding site” in claim 10.
Enablement
Claims 10, 11, 16, 22 remain 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 an isolated mammalian cell comprising a nucleic acid sequence encoding a transcription factor that binds to a bind site that allows transcription of a protein of interest, does not reasonably provide enablement for the claims as written. 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/use the invention commensurate in scope with these claims.
Claim 10 and its breadth are discussed above.
The metes and bounds of a “drug responsive domain” in claim 10 cannot be determined for reasons set forth above.
The art at the time of filing is discussed above.
Lines 1-3 of claim 10 require a nucleic acid sequence encoding a DRD and a sequence encoding a “transcription factor”, “wherein the transcription factor is operably linked to the DRD”. This does not make scientific, logical, or legal sense because there is no expression of the “transcription factor” or the DRD and because it is unclear if the “transcription factor” bound to the DRD is the “ligand” that makes the DRD stable (according to paragraph 153) or if it is some other entity. Lines 4-6 of claim 10 require the transcription factor is able to bind a “specific polynucleotide binding site” and activate transcription of a third sequence encoding a protein of interest operably linked to the “specific polynucleotide binding site”. Clarification is required for reasons set forth above. Overall, the metes and bounds of the structure and function of the modification in claim 10 cannot be determined.
Fig. 1A is limited to a DRD comprising a DNA binding domain (DBD), a transcription factor activation domain (TAD), and a drug responsive domain (DRD). This is completely missing from claim 10 and fails to explain the metes and bounds of what applicants consider a DRD. It is unclear whether claim 10 encompasses the DBD or TAD in Fig. 1A.
Fig. 1B discusses a “payload construct” with a DBD binding site, a minimal promoter, and a “payload”; however, it is unclear whether claim 10 encompasses any of these concepts.
Pg 89-92 discuss ligands for FKBP, DHFR, PDE5, CA2, or estrogen receptor.
Pg 92-101 discuss various “payloads” but it is unclear how they correlate to the elements of claim 10.
Pg 103-115 discusses delivering nucleic acids to cells.
Pg 118-142 discusses therapeutic uses, but it is unclear how the cell of claim 10 is therapeutic. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for therapeutic purposes. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for therapeutic purposes.
Pg 142-144 discusses “gene editing” uses, but it is unclear how the cell of claim 10 is used for “gene editing”. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for “gene editing” purposes. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for “gene editing” purposes.
Pg 144-152 discuss “other uses”, but it is unclear how the cell of claim 10 is used for “gene editing”. It is unclear how to use the cell of claim 10 to deliver a sequence encoding a “protein of interest” for “other uses”. It is unclear what the DRD and transcription factor have to do with any aspect of controlling or regulating delivery of the sequence encoding the “protein of interest” for “other uses”.
Definitions are on pg 152-179. No definition of DRDs can be found in this section.
Example 1 (pg 179) discusses the design of transcription factor systems and is limited to the structure in Fig. 1A and 1B:
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It is unclear from the discussion in Example 1 how to use the system, how to regulate expression of the “payload”, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 1 how to regulate or control expression of the “payload”. It is unclear from the discussion in Example 1 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 1 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 1 correlate to the elements in claim 10 and which elements in Example 1 are missing from claim 10. In fact, it is unclear what elements in Example 1 are required to obtain any desired functionality or regulation of expression. It is unclear whether the system is inducible or not. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload.
Example 2 (pg 183) discusses viral production and cell line generation. It is unclear from the discussion in Example 2 how to use the system, how to regulate expression of the “payload”, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 2 how to regulate or control expression of the “payload”. It is unclear from the discussion in Example 2 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 2 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 2 correlate to the elements in claim 10 and which elements in Example 2 are missing from claim 10. In fact, it is unclear what elements in Example 2 are required to obtain any desired functionality or regulation of expression. It is unclear whether the system is inducible or not. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload.
Example 3 (pg 184) discusses ligand-dependent regulation of transcription factors, but claim 10 does not require any ligand or that the DRD is expressed or that the DRD is controlled by any ligand. It is unclear from the discussion in Example 3 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 3 how to regulate or control expression of the “payload” using a ligand. It is unclear from the discussion in Example 3 how any protein is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 3 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 3 correlate to the elements in claim 10 and which elements in Example 3 are missing from claim 10. In fact, it is unclear what elements in Example 3 are required to obtain any desired functionality or regulation of expression using any ligand. It is unclear whether the system is inducible or not. If so, it is unclear whether the ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand that stabilizes DRD has anything to do with claim 10 or regulating expression of any “payload. However, the discussion in Example 3 is limited to using specific ligands that bind specific DRDs, but claim 10 makes no reference to any ligand.
Example 4 (pg 186) and 5 (pg 188) and 6 (pg 189) an 11 (pg 194) are specific for a ecDHRF DRD-regulated transcription factor system, but claim 10 does not require any ligand, specifically ecDHRF, or that the DRD is expressed or that the DRD is controlled by any ligand, specifically ecDHRF. It is unclear from the discussion in Example 4-6, 11 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 4-6, 11 how to regulate or control expression of the “payload” using a ligand, specifically ecDHRF. It is unclear from the discussion in Example 4-6, 11 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 4-6, 11 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 4-6, 11 correlate to the elements in claim 10 and which elements in Example 4-6, 11 are missing from claim 10. In fact, it is unclear what elements in Example 4-6, 11 are required to obtain any desired functionality or regulation of expression using any ligand, specifically ecDHRF. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand, specifically ecDHRF, is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of any “payload. The discussion in Example 4-6, 11 is limited to using a specific ligand, ecDHRF, which binds to specific DRDs, but claim 10 makes no reference to any ligand.
Example 7 (pg 190) and 8 (pg 192) and 9 (pg 192) and 10 (pg 193) and 12 (pg 195) and 14 (pg 198) are specific for a CA2 DRD-regulated transcription factor system, but claim 10 does not require any ligand, specifically ecDHRF, or that the DRD is expressed or that the DRD is controlled by any ligand, specifically ecDHRF. It is unclear from the discussion in Example 7-9, 11, 12 how to use the system, how to regulate expression of the “payload” using a ligand, or how the “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 7-9, 11, 12 how to regulate or control expression of the “payload” using a ligand, specifically ecDHRF. It is unclear from the discussion in Example 7-9, 11, 12 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 7-9, 11, 12 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 7-9, 11, 12 correlate to the elements in claim 10 and which elements in Example 7-9, 11, 12 are missing from claim 10. In fact, it is unclear what elements in Example 7-9, 11, 12 are required to obtain any desired functionality or regulation of expression using any ligand, specifically ecDHRF. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of any “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of any “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand, specifically ecDHRF, is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of any “payload. The discussion in Example 7-9, 11, 12 is limited to using a specific ligand, ecDHRF, which binds to specific DRDs, but claim 10 makes no reference to any ligand.
Example 16 (pg 200) discusses expressing IL-12 as the payload. However, the example is limited to using constructs ZFHD-005 (example 4) and ZFHD-13 which encodes IL-12. “Ligand treatment” is discussed on pg 200, para 703, but claim 10 does not require any ligand, that the DRD is expressed, or that the DRD is controlled by any ligand. It is unclear from the discussion in Example 16 how to use the system, how to regulate expression of the IL12 “payload” using a ligand, or how the IL12 “payload” correlates to the structures in claim 10. It is unclear from the discussion in Example 16 how to regulate or control expression of the IL12 “payload” using a ligand. It is unclear from the discussion in Example 16 how any DHRF is a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” or what that has to do with the structures/functions in claim 10. Example 16 is extremely limited as compared to the structures/functions in claim, but it is unclear what elements in Example 16 correlate to the elements in claim 10 and which elements in Example 16 are missing from claim 10. In fact, it is unclear what elements in Example 16 are required to obtain any desired functionality, expression of the IL12 “payload”, or regulate expression of an IL12 “payload” using any ligand. It is unclear whether the system is inducible or not. If so, it is unclear whether the DHRF ligand is inducing IL12 expression or whether it is something else. It is unclear how a DBD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” has anything to do with regulating expression of an IL12 “payload”. It is unclear how any transcription factor as broadly encompassed by claim 10 has anything to do with regulating expression of an IL12 “payload” because claim 10 does not necessarily require the ”transcription factor” is the ligand for the DRD. It is unclear how any ligand is capable of stabilizing any DRD or how it has anything to do with claim 10 or regulating expression of an IL12 “payload. The discussion in Example 16 does not teach the specific ligand that binds to the specific DRD, and claim 10 makes no reference to any ligand.
Example 17 (pg 201) discusses ligand-dependent regulation of FOXP3 transcription factors. Example 17 (pg 201) and 18 (pg 203) discuss ligand-dependent regulation of c-Jun transcription factors. Examples 17 and 18 are deficient for reasons set forth above.
Claim 10 encompasses using a sequence encoding an ecDHFR or CA2 DRD having the amino acid sequence of SEQ ID NO: 1 in Table 3 on pg 66 (or perhaps applicants are saying a DRD is a peptide “derived” from SEQ ID NO: 1 or 5) in combination with a sequence encoding any transcription factor that binds any binding site operably linked to a sequence encoding any protein of interest. However, claim 10 is missing any functional link between the elements that involve the ligand that is specific to the CA2 or DHFR DRD, and the specific transcription factor and specific binding site that induce expression of the protein of interest. None of the claims are limited to any specific CA2 or DHFR DRD, any specific ligand, or any specific binding site that would induce expression of a protein of interest. There are no teachings in the specification about how to operably link CA2 or DHFR DRD with a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain. There are no teachings in the specification about how to use a fusion protein comprising i) CA2 or DHFR DRD operably linked to ii) a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any [1st] nucleic acid sequence encoding a CA2 or DHFR DRD operably linked to a [2nd] sequence encoding a fusion transcription factor comprising a ZFHDA DNA binding domain and a p65 activation domain that binds a [3rd] sequence encoding a protein of interest operably linked to a [transcription factor] binding site as required in claim 10.
The specification does not enable making any species of cell in vitro or in vivo as broadly encompassed by claim 10 other than isolated mammalian cells. The specification does not teach or suggest doing so in invertebrate, insect, amphibian, reptile, or bird cells. The specification does not contemplate constructing the cells in vivo. Therefore, the claims should be limited to isolated mammalian cells.
The specification does not enable a nucleic acid encoding a protein of interest operably linked to an inducible promoter as required in claim 11. Looking to example 16 (pg 200) as the most specific example of a 3rd nucleic acid sequence encoding a protein of interest, there is no inducible promoter in the Example or in the ZFHD-005 or -013 constructs used to make the cells, and there is no inducer added to the cells that causes IL12 expression. Pg 201, para 703, is limited to “ligand treatment” which does not appear to allow expression of IL12, so the “ligand” for whatever DRD is in Example 16 does not involve an “inducible promoter” as required in claim 11. Therefore, the concept in claim 11 lacks written description.
The specification does not enable any DRD “derived” from CA2 or DHFR as required in claim 10 for reasons set forth above. The specification does not enable using any specific DRD “derived” from CA2 or DHFR in combination with any ZFHD1/p65 fusion transcription factor, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
The specification does not enable any CA2 or DHRF DRD “stabilized in the presence of” ACZ, MTX, or TMP as required in claim 16 for reasons set forth above. The specification does not enable using any CA2 or DHRF DRD “stabilized in the presence of” ACZ, MTX, or TMP in combination with any ZFHD1/p65 fusion transcription factor, any binding site, and any ligand as broadly encompassed by claim 16 for reasons set forth above.
The specification does not enable any transcription factor comprising a ZFHD1 DNA binding domain as required in claim 10. While ZFHD1 is a transcription factor and has a DNA binding domain, it is unclear when a DNA binding domain is “derived from” ZFHD1 as claimed. The specification does not enable using any “DNA binding domain” “derived from” ZFHD1 other than a ZFHD1 DNA binding domain. The specification does not enable using a ZFHD1 DNA binding domain in combination with any CA2 or DHFR DRD, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
The specification does not enable any transcription factor activation domain that is “derived from” p65 as required in claim 10. While p65 is a transcription factor and has an “activation domain”, it is unclear when an activation domain is “derived from” p65 as claimed. The specification lacks written description for using any “activation domain” “derived from” p65 other than a p65 activation domain. The specification does not enable using any p65 activation domain in combination with any CA2 or DHRF DRD, any binding site, and ligand as broadly encompassed by claim 10 for reasons set forth above.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Applicants point to case law. Applicants’ argument is not persuasive because the fact patterns in this case are not the same as those cases.
Applicants point to Examples 2, 3, 7, 10 which teach a fusion transcription factor comprising a DNA binding domain “derived from” ZFHD1 and an activation domain “derived from” p65. Applicants’ argument is not persuasive because the examples are limited to a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain. The phrase “derived from” encompasses anything that resembles and shares any structure or function of a ZFHD1 DNA binding domain or p65 activation domain. But applicants simply used a ZFHD1 DNA binding domain and p65 activation domain without any further “derivations”.
If applicants are attempting to say Examples 2, 3, 7, 10 taught a nucleic acid sequence encoding a fusion protein comprising i) a fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain operably linked to ii) a CA2 DRD or DHFR DRD, then please point to such a coding sequence/fusion protein specifically. Please also teach the function of the fusion protein, especially as it relates to the “nucleic acid sequence encoding a protein of interest” operably linked to a “specific [transcription factor] binding site” in claim 10.
Indefiniteness
Claims 10, 11, 16, 22 remain 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.
The metes and bounds of a CA2 or DHFR “drug responsive domain” (DRD) in claim 10 cannot be determined. The specification uses the term or the abbreviation DRD thereof multiple times from pg 1-65 without defining the metes and bounds. Para 153-155 on pg 65-66 discusses DRDs without defining them. Para 153 says they are “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” and is “interchangeable with the term destabilizing domain (DD)”. The paragraph goes on to say DRDs can be applied to proteins to make them unstable. Para 154 says DRDs may be derived from know proteins. However, this discussion is so scientifically confusing and vague as to be meaningless. An antigen may bind an antibody, but it is unclear how the antigen is “unstable and degraded” in the absence of a ligand. A portion of a protein may be antigenic and capable of binding an antibody, but it is unclear how the antigenic portion is “unstable and degraded” in the absence of a ligand. It is unclear what “well-known” proteins DRDs are ”derived from”. Para 155 says the “parent protein” may be DHFR or CA2 (pg 66); however, it is unclear how to derive any DRDs from DHFR or CA2. It is also unclear how to test any peptide derived from DHFR or CA2 to determine whether it “unstable and degraded in the absence of a ligand” “but whose stability is rescued by binding to a corresponding DRD-binding ligand”. The specification and the art at the time of filing do not teach when a fragment of DHFR or CA2 is “unstable” in the absence of a ligand. The specification does not teach any fragments of DHFR or CA2 that degrade in the absence of a ligand. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
The metes and bounds of a DRD “derived from” CA2 or DHFR in claim 10 cannot be determined. It is unclear whether the phrase is limited to a CA2 or DHFR DRD or if it encompasses derivatives thereof. If the phrase encompasses “derivatives” of CA2 or DHFR DRD, then it is unclear when a DRD remains “derived from” CA2 or DHFR and when it is no longer “derived from” CA2 or DHFR DRD.
Response to arguments
Applicants argue the structures/funcitons are clear from paragraphs 107-135, table 1, para 324, 343-508. Applicants’ argument is not persuasive. None of the paragraphs cited teach the fusion transcription factor in claim 10. None of the paragraphs cited teach a fusion protein comprising a CA2 or DHFR DRD operably linked to a ZFHD1/p65 fusion transcription factor.
Claims 10, 11, 16, 22 remain rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: i) functional language that limits the structure/function of CA2 or DHFR DRDs (i.e. “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand” (however, this would still be indefinite because the limits of when a protein is “unstable” or “degraded” in the absence of a ligand have not been defined in the specification or the art at the time of filing); ii) the ligand that specifically binds a protein that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand”; iii) a nexus between the “ligand” contemplated in the specification and the system in claim 10 as a whole, specifically the transcription factor in claim 10; iv) the fact that the CA2 or DHFR DRD is a co-expressed in context of fusion protein with a ZFHD1/p65 fusion transcription factor (Fig. 1A); v) the fact that the “specific polynucleotide binding site” is actually a binding site for a transcription factor, vi) the fact that the “specific polynucleotide binding site” is actually a binding site for a ZFHD1 DNA binding domain; vii) and possibly more.
Claim 10 is indefinite because it requires “a first nucleic acid sequence encoding a [DRD] and a second nucleic acid sequence encoding a transcription factor, wherein the transcription factor is operably linked to the DRD”. The phrase does not make sense. While the nucleic acid sequence encoding the DRD and the nucleic acid sequence encoding a transcription factor may be operably linked, there is nothing that requires expression of the fusion transcription factor, the DRD, or a fusion protein comprising the fusion transcription factor and the DRD in claim 10. The nucleic acid sequence encoding the DRD and the nucleic acid sequence encoding a transcription factor may encode a fusion protein comprising the DRD and the transcription factor, there is nothing in claim 10 that requires expression of a fusion protein. The nucleic acids may encoding a fusion protein comprising the DRD and the transcription factor, but it is wholly unclear how/when a “DRD” and transcription factor are “operably linked”. Accordingly, the structures/functions associated with the modification in the cell of claim 10 cannot be determined.
The metes and bounds of a “specific polynucleotide binding site” in claim 10 cannot be determined. While a transcription factor may bind to a polynucleotide binding site and allow for transcription of a protein of interest, it is unclear how/when the binding site is “specific”.
The metes and bounds of when a “specific polynucleotide binding site” is an “exogenous inducible promoter” in claim 11 cannot be determined. Since a transcription factor already “induces” transcription of a protein of interest upon binding the response element of the coding sequence of the protein of interest, it is unclear how the concept of an “inducible promoter” differs from a specific binding site that causes expression of the protein of interest.
The metes and bounds of when a DRD is “derived” from CA2, DHFR, ER, FKBP, or PDE5 as required in claim 15. The metes and bounds of a DRD are unclear for reasons set forth above, and the assay required to determine when a DRD has been obtained have not been clearly set forth in the specification and cannot be found in the art at the time of filing. It is unclear if the phrase encompasses any entire CA2, DHFR, ER, FKBP, or PDE5 protein or if the concept is limited to fragments. It is unclear if the phrase encompasses any CA2, DHFR, ER, FKBP, or PDE5 fragment or if the concept is limited to fragments having specific structures/functions. If the concept is limited to fragments having specific structures/functions, then it is unclear what structures/functions define when a DRD has been “derived” from CA2, DHFR, ER, FKBP, or PDE5. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
The metes and bounds of when a DRD is “stabilized” in the presence of a ligand that is ACZ, MTX, or TMP as required in claim 16. None of the claims require the presence of a ligand of any kind. It is unclear how the presence of the ligand further limits the structure/function of the DRD. It is unclear how a ligand that “stabilizes” the DRD has a nexus with a DRD that is “unstable and degraded in the absence of a ligand, but whose stability is rescued by binding to a corresponding DRD-binding ligand”. It is unclear if the term “stabilizes” means the ligand improves stability of the DRD or if it means the RDR is “stable” as opposed to “unstable”. However, the metes and bounds of when an RDR is “stabilized” vs. “unstable” is not defined in the specification or the art at the time of filing because the term is relative, because the specification and art do not teach an assay for determining when and RDR is “stable” vs. “unstable”, and because the specification and art do not teach the amount of stability/instability that defines when and protein or RDR is “stabilized”. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
Response to arguments
Applicants argue the claim as amended overcomes the rejection. Applicants’ argument is not persuasive. There is no nexus between the nucleic acids encoding the fusion transcription factor or [possibly] a fusion protein comprising i) a CA2 or DHFR DRD and ii) fusion transcription factor comprising a ZFHD1 DNA binding domain and a p65 activation domain. There is no nexus between the transcription factor and the DNA binding site operably linked to the 3rd nucleic acid encoding the protein of interest. It is unclear whether the 3rd nucleic acid is in the cell or not.
Claim Rejections - 35 USC § 102
The rejection of claims 10, 11, 16, 22 under 35 U.S.C. 102a1 as being anticipated by Zhang (WO 2016106244) has been withdrawn. Zhang is limited to a cell comprising a nucleic acid sequence encoding Cas9 operably linked to a nucleic acid sequence encoding a destabilizing domain (DD) capable of expressing a fusion protein comprising Cas9 and the DD, wherein the fusion protein is capable of binding a specific target site and inducing expression of a protein of interest (para 13, 48). The DD may be derived from DHFR; the ligand may be TMP (para 13). Cas9 may have transcription activators, e.g. VP64 of p65, attached (para 48). Zhang did not teach a sequence encoding a fusion ZFHD1/p65 transcription factor as required in claim 10 or operably linking a fusion ZFHD1/p65 transcription factor to DHFR DD as possibly encompassed by claim 10.
The art at the time of filing did not reasonably teach or suggest a cell comprising a nucleic acid sequence encoding a fusion ZFHD1/p65 transcription factor as required in claim 10 or operably linking a fusion ZFHD1/p65 transcription factor to DHFR DD as possibly encompassed by claim 10.
Conclusion
No claim is allowed.
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.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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