DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 88-107 are pending as amended 12/7/2023, and are considered herein.
Formalities:
The drawings are again objected to, for containing color. See below.
Drawings
The drawings are objected to.
Figures 2-3, 11, 13-15, 20-24, and 29-34 contain color.
While the specification contains a statement in the brief description of the color drawings, there is no petition in the file to accept color drawings. The Examiner assumes the drawings have been filed in the electronic filing system. If this is incorrect, Applicant should also file two more sets of color drawings.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Response to Argument – color drawings
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues that a petition was filed for color drawings, and thus, the drawings are acceptable now (p. 5, paragraph 4).
Such is not persuasive. The office denied the petition, and Examiner cannot question the office’s decision. Thus, the objections the drawings remain.
Claim Objections
In light of the amendment correcting the spelling of “kinase”, the objection to Claim 91 is withdrawn.
Applicant is again advised that should claim 101 be found allowable, claim 102 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 102 limits the cancer cell to being transduced in vivo by administration of the retroviral vector. However, this is limiting to Claim 101, which recites “a cancer cell of interest in a patient”. If it is in the patient, it is in vivo. Thus, despite a slight difference in wording, these claims have substantially the same scope.
In light of the cancelation of Claim 106, the advisory that should claim 101 be found allowable, claim 106 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof, is withdrawn.
Response to argument – Claim Objection Advisory
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues that the method of Claim 101 is to inducing cell killing in a cancer, by contacting the cell with a retroviral vector particle and subsequently the nucleotide analog or prodrug, and that the Artisan would not recognize it can only be carried out in vivo, citing the specification (p. 6, paragraph 2).
Such is not persuasive. The specification has nothing to do with the claimed scope. Claim 101 literally states “A method of inducing cell kill activity in a cancer cell of interest in a patient”. The Examiner sees no other interpretation of the claim, but that the “cancer cell of interest” is “in a patient” (emphasis added.). There is no removal of the cell from the patient, then transfection. In this case, it is clear that preamble is controlling.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
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.
The rejections of Claims 92 and 101 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, are withdrawn.
In light of the amendment to Claim 92, the rejection of the same for nested ranges, is withdrawn. (It is noted that the Examiner mistakenly forgot to add such claim to the form paragraph, and thanks Applicant for correcting it.)
In light of the amendment to Claim 101, the rejection of Claim 101 for “contacting the cancer cell with a retroviral vector of Claim 94” then “transducing the cancer cell with the polynucleotide encoding the mutated thymidine kinase”, is withdrawn
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
In light of further consideration, the rejection of Claim 104 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn.
To wit, the claims lists several methods of administration, and Claim 101 is any form of administration.
Claim 103 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 101 requires the cell to be within the subject, i.e., “…in a cancer cell of interest in a patient”. Claim 103 depends from Claim 101, but states the “the cancer cell in (a) is transduced in vitro by contacting … obtained from the patient … wherein the contacting … occurs outside the patient, and … subsequently administered to the patient …”. Such is outside the scope of Claim 101. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 88-107 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are generic for an HSV1-TK comprising an NLS of amino acids 1-33 of SEQ ID NO: 2, where either (i) amino acids 25-26, (ii) amino acids 32-33 or (iii) amino acids 25-33 are deleted, where the cell killing activity of the HSV1-TK is increased compared to wild-type HSV1-TK.
The specification teaches mutations of amino acid pairs (i) and (ii) as well as 25, 26, 32, and 33 (e.g., paragraph 7). Additionally, regarding deletions, it is taught to delete the N-terminal 45 amino acids of TK mutants to construct a truncated form (e.g., paragraph 201), and mutations may be introduced into TK, which include deletions (e.g., paragraph 221), and the use of mutagenesis to generate any form of substitution, deletion or insertion (e.g., paragraph 222). However, there is no direction to delete amino acids 25-26, 32-33, or 25-33 of HSV1-TK NLS of SEQ ID NO: 2, to arrive at the invention. To arrive at such would be obviousness, which is not a demonstration of possession.
The earliest art for mutants in this field is Applicant’s priority chain, and this does not produce any more information to direct the Artisan to these mutants.
Thus, given the generic teachings in the specification, and lack of antecedent basis to direct the Artisan to specifically claimed NLS deletion mutants, the Artisan would not have understood Applicant to have been in possession of the invention.
Response to Argument – deletions at 25-26, 32-33, and 25-33 of NLS
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues paragraph 148 supports nucleotides encoding HSV-TK, where it is mutated at 25, 26, 32, 33, 167, 168, or a combination thereof and paragraph 122 provides the sequence encodes derivatives having insertion, substitution, or deletion; and this provides the support for deletions at 25-26 and 32-33 (pp. 6-7, paragraph bridging).
Such is not persuasive. This are a number options, from the Markush of 6 amino acids, and there is not even a direction to pairs next to each other. Further, on top of the 19 amino acids possible to mutate only, it is further confounded by Applicant’s assertion of description here, in that the mutation may be a insertion, a deletion, or substitution [i.e., deletion and insertion at the same spot]. Given the number of possibilities, Applicant’s support appears to be an obviousness type support: i.e., it is within the broad scope described, so its obvious. This is not the blaze marks of possession, which would direct to the specific pairs of amino acids, and a further elucidation of whether it is meant to be mere changes at these positions to another amino acid, or if it also means deletions, given that paragraph 148 states “mutated”.
Applicant cites paragraph 493, arguing it depicts NLS removal, and Figure 21 demonstrates that amino acid residues 25-33 are in the NLS, and thus provide support for deletions (p. 7, paragraph 2).
Such is not persuasive. Paragraph 493 teaches NLS removal, but does not direct the Artisan to delete only amino acids 25-33. This is not the blaze marks of possession. It is an obviousness type support.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
Claim(s) 91-95 is/are rejected under pre-AIA 35 U.S.C. 102(a) as being anticipated by Hsieh, et al. (2008) “Generation of Destabilized Herpes Simplex Virus Type 1 Thymidine Kinase as Transcription Reporter for the PET Reporter Systems in Molecular-Genetic Imaging”, The Journal of Nuclear Medicine, 49(1): 142-50.
Claim 88: Hsieh teach pCMV-mNLSHSV1-TK:dMODC and pCMV-mNLSHSV1-TK plasmids, which includes a mutated NLS, where amino acids 25-26 are mutated to glycine and serine, respectively. As far as the activity, because it is not imported to the nucleus, it is assumed to have such activity.
Claim 91: absent reason to believe otherwise, there is reduced kinase activity, in the nucleus, as it is not imported.
Claim 92: absent reason to believe otherwise, the activity in the nucleus is reduced by at least 1.5%.
Claim 93: with the mutated NLS, the TK does not so-localize.
Claim 94: The pRevTRE is a retroviral vector (pp. 143-44, paragraph briding).
Claim 95: the pRevTRE retrovial vector contains a truncated gag protein coding region (official notice), which could be considered therapeutic, as it can elicit an immune response. Thus, it is therapeutic.
Response to Argument – 102, Hsieh
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues that Hsieh teaches mutated amino acids, where it is replaced with glycine, but does not teach deletion (p. 9, paragraph 4).
Such is not persuasive. The structure of the NLS is one in which the amino acids were deleted, then replaced. Given the broadest reasonable interpretation, such comprises a deletion of the amino acids at the positions, in the structure made.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
Claim(s) 88 and 91-93 is/are rejected under pre-AIA 35 U.S.C. 102(a) as being anticipated by Degreve, et al. (1998) “Differential Intracellular Compartmentalization of Herpetic Thymidine Kinases (TKs) in TK Gene-Transfected Tumor Cells: Molecular Characterization of the Nuclear Localization Signal of Herpes Simplex Virus Type 1 TK”, Journal of Virology, 72(12): 9535-43.
Claim 88: Degreve teaches plasmids encoding HSV1-TK and HSV2-TK, where amino acids 1 to 34 are deleted (p. 9538, col. 2, paragraph 2). Absent reason to believe otherwise, the activity is found, as the structure is met.
Claim 91: as it is not imported to the nucleus, it is assumed that the activity is reduced in the nucleus.
Claim 92: As it is not imported, it is assume the activity is reduced at least 1.5% in the nucleus.
Claim 93: as the NLS is gone, it is assume not to localize exclusively to the nucleus.
Response to Argument – 102, Degreve
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues that Degreve deletes amino acids 1-33, while claim 88 is to deletions of of a Markush of 25-26, 32-33 or 25-33 (p. 10, paragraph 2).
Such is not persuasive. The amino acids are deleted, and such meets the broadest reasonable interpretation of the claimed Markush of amino acids. Further, Applicant actually uses the whole region of the NLS to say it provides support for deleting amino acids 25-33, when arguing the description rejections (Applicant’s argument of 8/20/25, p. 7, paragraph 2). These arguments conflict with us, as if Applicant’s description of the whole NLS actually provides support for a claimed deletion, then Degreve must teach the claimed deletion.
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.
Claims 88 and 91-93 rejected under 35 U.S.C. 101 because the claimed invention lacks patentable utility.
As shown in Degreve, et al. (1998) “Differential Intracellular Compartmentalization of Herpetic Thymidine Kinases (TKs) in TK Gene-Transfected Tumor Cells: Molecular Characterization of the Nuclear Localization Signal of Herpes Simplex Virus Type 1 TK”, Journal of Virology, 72(12): 9535-43, varicella-zoster virus (VZV) encodes a thymidine kinase (e.g., p. 9535, col. 1, first paragraph). The same is known to have the structure corresponding to 1-33 of SEQ ID NO: 2 to be missing (Figure 2). Moreover, as it is a thymidine kinase, it can be considered a TK that is mutated in form, compared to HSV1-TK. Further, the activity is assumed to be present, as the structure is present.
Thus, the claimed invention exists in nature.
Response to Argument – 101, exists in nature
Applicant’s argument of 8/20/25 has been considered but is not found persuasive.
Applicant argues that the Artisan would not conclude that the HSV-1 TK and VZV TK are homologous, much less the same, as evidenced by the sequence alignment. Further, it odes not teach the specific deletions (pp. 8-9, paragraph bridging).
Such is not persuasive. The Examiner has not argued they are the same. What is argued is that the VZV TK is thymidine kinase, and as such has the structure of a functioning thymidine kinase, which is mutated into the form of thymidine kinase. With regard to the deletions, it is also argued that the structure is the same, as one containing those deletions.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638