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 .
The Examiner notes that the prior Non-Final Office Action, mailed 10/29/2025, is vacated and replaced by this Non-Final Office Action.
Election/Restrictions
Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/29/2025.
Applicant’s election without traverse of SEQ ID NO: 3 (furin site – RRKR) and SEQ ID NO: 4 (T2A peptide – EGRGSLLTCGDVEENPGP) in the reply filed on 9/29/2025 is acknowledged.
Applicant's election with traverse of thymidine kinase in the reply filed on 9/29/2025 is acknowledged. The traversal is on the ground(s) that mutant thymidine kinase (claim 20) is a subspecies of thymidine kinase in claim 19. This is found persuasive.
Claims 1-5, 14-17, 19, 20, 23, and 34-38 are pending and under examination
Priority
This application is a continuation of application 18/049,266, filed on 10/24/2022, now U.S. Patent 12,234,475. Applicant’s claim for the benefit of a prior-filed application provisional applications 63/413,165 filed on 10/04/2022 and 63/271,674 filed on 10/25/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/15/2025 and 10/01/2025 are considered by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract filed on 9/19/2024 only contains 23 words. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 20, 23, and 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 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 20 and 38 recite “wherein the thymidine kinase is in a mutated form with increased cell kill activity relative to a wild-type thymidine kinase”.
In analyzing whether the written description requirement is met for genus, such as a mutated form of thymidine kinase, the specification is first assessed to determine whether a representative number of species (i.e., mutated thymidine kinases) have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The specification discloses the following:
[0042] In some aspects, the thymidine kinase described herein can be a mutant thymidine kinase, where the mutant thymidine kinase comprises at least one amino acid mutation. In some aspects, the mutant thymidine kinase is a mutant Herpes Simplex Virus type 1 thymidine kinase (HSV1-TK) comprising at least one amino acid mutation compared to wild type amino acid sequence of HSV1-TK…In some aspects, the mutant HSV1-TK comprises an amino acid sequence that is at least 75%, 76%,77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%,93%,94%,95%, 96%,97%, 98%,99%, or more sequence identity to the HSV1-TK amino acid sequence (e.g., SEQ ID NO: 1). In some embodiments, the mutant HSV-1-TK comprises a nuclear export sequence (NES). In some aspects, the NES comprises an amino acid sequence of LQKKLEELELDG (SEQ ID NO: 2).
[0043] In some embodiments, the mutant HSV1-TK comprises at least one amino acid mutation at amino acid residue 25, 26, 32, 33, 167, 168, or a combination thereof compared to the wild type amino acid sequence of HSV1-TK (SEQ ID NO: 1). In some embodiments, the mutation comprises substituting a wild type amino acid with a polar, non-polar, basic or acidic amino acid. In some embodiments, the mutant HSV1-TK is mutated at amino acid residues 167, 168, or both. In one example, the sequence is mutated at amino acid residue 167. In another example, the sequence is mutated at amino acid residue 168. In another example, the sequence is mutated at amino acid residues 167 and 168.Amino acid residue 167 may be mutated to histidine, lysine, cysteine, serine, and phenylalanine. Amino acid residue 168 may be mutated to histidine, lysine, cysteine, serine, or phenylalanine. In some embodiments, the mutant HSV1-TK is mutated at amino acid residues 25 and/or 26. In amino acid residues 25 and/or 26 may be mutated to an amino acid chosen from the group consisting of: glycine, serine, and glutamate. In some embodiments, the mutant HSV1-TK is mutated at amino acid residues 32 and/or 33. Amino acid residues 32 and/or 33 may be mutated to an amino acid chosen from the group consisting of: glycine, serine, cysteine, glutamic acid, and aspartic acid. In some embodiments, the mutant HSV1-TK is mutated at amino acid residues 25, 26, 32, and/or 33. Amino acid residues 25, 26, 32, and/or 33, may be mutated to an amino acid chosen from the group consisting of: glycine, serine, cysteine, glutamic acid, and aspartic acid.
[0044-0048] discloses additionally embodiments of the mutant HSV1-TK.
[0126] As used herein, the term "mutant thymidine kinase" refers to not only the specific protein described herein (as well as the nucleic acid sequences which encode these proteins), but derivatives thereof which may include various structural forms of the primary protein which retain biological activity.
The claims are broad for reciting a genus of mutated thymidine kinases. As written, any number of bases/amino acids in the thymidine kinase may be altered in any way, including but not limited to mutations such as deletions, substitutions, and frameshifts, resulting in an enormously vast genus of possible mutant thymidine kinase variants.
Given the breadth of a thymidine kinase in a mutated, a reiteration of the claim limitation, definition of “mutant thymidine kinase”, and list of possible embodiments does not represent an adequate disclosure of the complete structure of the vastly broad genus.
The prior art does not inform the ordinary artisan of the structure/function nexus, let alone which mutations of thymidine kinase will retain the claimed function(s) (e.g., increasing cell kill activity relative to a wild-type thymidine kinase), as opposed to which modifications will not retain the claimed function(s).
Malartre, Nicolas, et al. "Effects of mutations on herpes simplex virus 1 thymidine kinase functionality: an in vitro assay based on detection of monophosphate forms of acyclovir and thymidine using HPLC/DAD." Antiviral research 95.3 (2012): 224-228 is considered relevant prior art for investigating the effects of mutations on herpes simplex virus 1 thymidine kinase functionality. Malarte teaches that resistance to acyclovir (ACV) is associated with mutations in UL23 thymidine kinase (TK) gene in 95% of cases (pg. 224, col 1), and “the considerable variety in UL23 TK polymorphism and the presence of several mutations in resistant strains can make it difficult to clearly identify whether or not these mutations are directly correlated to ACV resistance” (i.e., alter their functionality) (pg. 224, col 2, para 1).
When discussing the characterization of different TK mutant proteins (“TKs were characterized as TK deficient (TKd) [ACV /dT ], TK altered (TKalt) [ACV / dT 15–100%] and TK low-producer (TKlow) [ACV /dT 1–15%] phenotypes (Gaudreau et al., 1998; Hill et al., 1991). Of note, the TKlow phenotype can be considered as a TKalt phenotype with less than 15% of dT phosphorylated”- pg. 225, col 2, para 1), Malarte notes “Enzymatic activity of TKs showed that A189V and L227F mutations induce a TKalt phenotype (Chibo et al., 2004), whereas G200S and L291P mutations induce a TKd phenotype (Table 1) (Duan et al., 2009; Gaudreau et al., 1998). Interestingly, G200S and L291P mutants were produced in a less soluble form than other TK proteins, probably reflecting their harmful impact on TK functionality (Fig.1A). P84L and A175V mutations in site 2 (Saijo et al., 2002; Sauerbrei et al., 2010) and in the nucleoside binding site (Frobert et al., 2005; Morfin et al., 2000), respectively, were shown to induce a TKalt phenotype” (pg. 225-227). Additionally, “the R163H mutant (site 3, (Sauerbrei et al., 2010)), which had 100% dT phosphorylating activity associated with only 10% of ACV phosphorylating activity suggests a ‘‘TK partial’’ phenotype that has never been described before” (pg. 227, col 1, para 1).
In summary, Malarte teaches that different mutations in TK result in different functionalities that are still being characterized.
The specification does not teach how thymidine kinase can be modified and still maintain the same function (i.e., how can the structure of the sequence change but still increase cell kill activity relative to a wild-type thymidine kinase?). Can parts (if any) of the kinase be deleted? Substituted? Where in the sequence would these modifications occur? Can any nucleotides be added to the sequence? If so, where would these insertions be in the sequence? With the provided specification, one of ordinary skill in the art cannot determine what parts of the polynucleotide sequence must be conserved in order to maintain the functions of thymidine kinase. Altering a sequence (i.e., altering the structure) could significantly impact or change the resulting function. Therefore, the specification fails to provide adequate written description of a representative number of species to describe the complete structure of the genus of thymidine kinase in a mutated form.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. These claims are usually handled in Technology Center 1600. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id. The Amgen decision will be added to the MPEP in due course.
A “representative number of species” means that the species which are adequately described are representative of the entire 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the thymidine kinase is to be mutated does not tell you anything at all about the structure (polynucleotide sequences) of the enormously vast genus of structurally undisclosed variants having the functional property of increasing cell kill activity relative to a wild-type thymidine kinase.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of thymidine kinase variant(s) includes an enormously vast genus of thymidine kinases in any a mutated form with the functionality of increased cell kill activity relative to a wild-type thymidine kinase
Also, when determining if the specification provides adequate written description for a
genus, it is determined whether a representative number of species have been sufficiently
described by other relevant characteristics, specified features and functional attributes that
would distinguish different members of the claimed genus. The only teachings provided by the specification are the embodiments found in [0042-0048], which includes but does not limit the mutated thymidine kinase to mutant HSV1-TK comprising at least one amino acid
mutation at amino acid residue 25, 26, 32, 33, 167, 168, or a combination thereof compared to the wild type amino acid sequence of HSV1-T. Again, there is a lack of disclosure of in the specification and thus it fails to describe other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus as required.
Given the breadth of the genus, species have not been sufficiently described by other relevant characteristics, specified features and functional attributes, and no working examples were provided. Given that no specific identifying features/characteristic of species of the genus were provided, the written description requirement disclosing the complete structure of genus, thymidine kinases in a mutated form, has not been met. Furthermore, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of the genus, thymidine kinases in a mutated form, at the time the application was filed.
Claim 23 recites the P35 subunit of the recombinant retroviral vector having the function of modulating expression of IL-12 in a cell.
Either this is an inherent property of (that naturally flows from) the P35 subunit of the recombinant retroviral vector of independent claim 1, or it is not.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language.
The limitation “wherein, upon expression of the P35 subunit in a cell, the P35 subunit modulates expression of IL-12 in the cell” merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the functional characteristic. The specification fails to disclose what structural changes to the P35 subunit is necessary and sufficient to cause the recited modulation of expression of IL-12 in a cell, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
In analyzing 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. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose a first P35 subunit of the recombinant retroviral vector that is unable to modulate expression of IL-12 in the cell, as opposed to a second P35 subunit that is necessarily and predictably capable of modulating expression of IL-12 in the cell, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first P35 subunit of the recombinant retroviral vector, that is unable to modulate expression of IL-12 in the cell, transforms said first P35 subunit into one that is now necessarily and predictably capable of modulating expression of IL-12 in the cell, for example.
Example 2 (pg. 41-42) of the specification teaches determining the effect of a retroviral vector designed to encode and express the P35 subunit of IL-12 on the expression of IL-12. The example teaches that increased expression of P35 alone causes increased expression of IL-12 [0146]. Claim 23, however, recites that P35 modulates IL-12 expression, which encompasses other changes to IL-12 expression, not just an increase. While the specification describes that P35 expression leads to increased IL-12 expression, it does not describe others ways to modulate IL-12 expression.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
Claim Rejections - 35 USC § 112(b)
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 34 is 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.
Claim 34 recites “a recombinant virus comprising the recombinant retroviral vector of claim 1”. In the art, a viral vector is considered a modified virus (i.e., viral vector is a type of virus) (see Viral Vector – Wikipedia reference), so it is unclear what the metes and bounds of this claim are and how the limitation of claim 34 differs from those recited in claim 1. A search of “recombinant virus” is the specification returned no results, offering no further guidance. For examination purposes, claim 34 is interpreted to comprise the same limitations as claim 1 (e.g., a viral vector reads on a virus).
Claim Rejections - 35 USC § 112(d)
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.
Claims 23 and 34 are 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 23 recites the P35 subunit of the recombinant retroviral vector having the function of modulating expression of IL-12 in a cell.
Either this is an inherent property of (that naturally flows from) the P35 subunit of the recombinant retroviral vector of independent claim 1, or it is not, and something of the structure of the P35 subunit of independent Claim 1 must change.
To the extent it is an inherent property of (that naturally flows from) the product/method of the independent claim, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the "wherein, upon expression of the P35 subunit in a cell, the P35 subunit modulates expression of IL-12 in the cell" clause does not recite any additional structures, but simply states a characterization or conclusion of the results of the structure positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims.
See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The specification fails to disclose a P35 subunit that is capable of expressing in a cell, yet does NOT also modulate expression of IL-12 in the cell.
Additionally, claim 34 recites “a recombinant virus comprising the recombinant retroviral vector of claim 1”. As discussed in the 112(b) rejection above, in the art, a viral vector is considered a modified virus (i.e., viral vector is a type of virus) (see Viral Vector – Wikipedia reference). Therefore, claim 34 is interpreted to comprise the same limitations as claim 1 (e.g., a viral vector reads on a virus).
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 § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 5, 14-17, 23, and 34-36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Precigen (US 2020/0283778, published 9/10/2020, #023 of IDS filed 5/15/2025).
Regarding Claim 1, Precigen discloses a recombinant retroviral vector (a vector that comprises the polynucleotide(s) of any of the compositions as provided herein. In an embodiment, the vector is a lentivirus vector, a retroviral vector, [0016]) comprising a nucleic
acid construct comprising a first polynucleotide sequence encoding P40 subunit of lnterleukin-12 (IL-12), a second polynucleotide sequence encoding P35 subunit of Interleukin-12, and a third polynucleotide sequence between the first and second polynucleotide sequences, wherein the third polynucleotide sequence encodes a cleavage site that facilitates cleavage between P40 subunit and P35 subunit (Fig. 21-25; at least one of the one or more polynucleotides ... provided herein further encodes a cytokine, [0021]; the cytokine is at least one of... IL-12, ... IL-12 is human single chain IL-12 (p40-linker-p35) [0209]; the linker polypeptide comprises disclosed in the table below: TABLE 1, [0156]-[0157]; TABLE 1 discloses a Furin-GSG-T2A linker).
Regarding Claim 2, Precigen discloses the recombinant retroviral vector of claim 1, wherein the cleavage site comprises a furin cleavage site (the linker polypeptide comprises disclosed in the table below: TABLE 1, [0156]-[0157]; TABLE 1 discloses a Furin-GSG-T2A linker).
Regarding Claim 4, Precigen discloses the recombinant retroviral vector of claim 1, wherein the nucleic acid construct further comprises a fourth polynucleotide sequence between the first and second polynucleotide sequences, wherein the fourth polynucleotide sequence
encodes a self-cleaving peptide (the linker polypeptide comprises disclosed in the table below: TABLE 1, [0156]-[0157]; TABLE 1 discloses a Furin-GSG-T2A linker).
Regarding Claim 5, Precigen discloses the recombinant retroviral vector of claim 4, wherein the self-cleaving peptide comprises an amino acid sequence sharing 100% identity with instant SEQ ID NO: 4 (EGRGSLLTCGDVEENPGP) (the linker polypeptide comprises disclosed in the table below: TABLE 1, [0156]-[0157]; TABLE·1 discloses a Furin-GSG-T2A linker comprising SEQ ID NO: 154; SEQ ID NO: 154 of Precigen comprises 100% sequence identity of instant SEQ ID NO: 4).
Regarding Claim 14, Precigen discloses the recombinant retroviral vector of claim 4. wherein the third polynucleotide sequence is upstream to the fourth polynucleotide sequence (the linker polypeptide comprises disclosed in the table below: TABLE 1, [0156]-(0157]; TABLE 1 discloses a Furin-GSG-T2A linker wherein the furin is upstream to the T2A).
Regarding Claim 15, Precigen discloses the recombinant retroviral vector of claim 4, wherein the nucleic acid construct further comprises a fifth polynucleotide sequence between the third and fourth polynucleotide sequences, wherein the fifth polynucleotide sequence encodes amino acid sequence GSG (the linker polypeptide comprises disclosed in the table below:
TABLE 1, [0156]-(0157]; TABLE 1 discloses a Furin-GSG-T2A linker).
Regarding Claim 16, Precigen discloses the recombinant retroviral vector in claim 1, wherein the first polynucleotide sequence is upstream to the second polynucleotide sequence (Fig 21A, part A; [0021]; the cytokine is at least one of ... IL-12, ... IL-12 is human single chain IL-12 (p40-linker-p35), [0209]).
Regarding Claim 17, Precigen discloses the recombinant retroviral vector in claim 16, wherein the nucleic acid construct comprises a first start codon immediately upstream to the first polynucleotide sequence, and a second start codon immediately upstream to the second
polynucleotide sequence (FIG. 23 schematically illustrates various structural components of diverse ligand-inducible gene switch vector systems to express different forms of IL-12 under the control of constitutive, inducible promoters or tissue-specific promoters (PR). IL-12
can be expressed as a single chain IL-12, [0095]; FIG. 23 discloses IL-12p40 upstream of IL-12p35 with separate start codons; The region or sequence is bounded nearer the 5' end by a start codon, [0129]; "Promoter" refers to a region of a polynucleotide that initiates transcription of a coding sequence. Promoters are located near the transcription start sites of genes, [0177]).
Regarding Claim 23, Precigen discloses the recombinant retroviral vector of claim 1, wherein, upon expression of the P35 subunit in a cell, the P35 subunit modulates expression of IL-12 in the cell (Fig 22, XON-61 and XON-62 comprise scIL-12 – according to Fig. 21A and [0095 and 209], scIL-12 includes p40-linker-p35). Absent evidence to the contrary, one of ordinary skill in the art would conclude the disclosure of Precigen reads on expression of the P35 subunit in a cell, as when scIL-12 is expressed, P35 is as well (Figs. 27-31 show IL-12 expression after cells transfected with recombinant retroviral vectors XON-61 and XON-62).
Regarding Claim 34, as stated above in the 112(b) rejection, the art, a viral vector is considered a modified virus. Therefore, Precigen discloses a recombinant virus comprising the recombinant retroviral vector of claim 1 (see rejection of claim 1 above).
Regarding Claim 35, Precigen discloses a cell comprising the recombinant retroviral vector of claim 1 or the recombinant virus of claim 34 (e.g., effector cell, target cell) [0051, 0052, 0066, 0069, 0213].
Regarding Claim 36, Precigen discloses a pharmaceutical composition comprising (i) the recombinant retroviral vector of claim 1, and (ii) a pharmaceutically acceptable carrier [0397, 0403, 418].
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Precigen as applied to claims 1, 2, 4, 5, 14-17, 23, and 34-36 above, and further in view of Fang (US7632509B2, published 12/15/2009).
Regarding Claim 3, Precigen does not teach the furin cleavage site comprising an amino acid sequence of SEQ ID NO: 3. The furin cleavage site taught by Precigen has an amino acid sequence of RAKR (see Table 1).
Fang teaches a furin cleavage site comprising RRKR (instant SEQ ID NO: 3) (SEQ ID NO: 16 of Fang) (Col. 15, Lns. 33-36). Fang teaches the furin cleavage site as part of a recombinant retroviral (i.e., lentiviral) vector comprising: promoter-heavy chain-furin-2A-light chain (Fig. 1; col 2, lines 32-46). Fang also teaches the 2A-mediated cleavage of a heterologous polyprotein has been shown for IL-12 (col 11, lines 9-16). Additionally, Fang teaches producing a lentivector comprising furin cleavage site RAKR, the same as used in Precigen.(col 29, lines 51-58; col 114, lines 16-33).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the furin cleavage sequence (i.e., RAKR) taught by Precigen with the furin cleavage sequence (i.e., RRKR) taught by Fang with a reasonable expectation for success.
An artisan would have a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute the siRNA nucleic acid solution with a mRNA nucleic acid solution in a method of encapsulating mRNA in lipid nanoparticles because MacLachlan et al disclosed the nucleic nucleic acid may be DNA, siRNA, or mRNA, and Guild et al (Applicant’s own work) had successfully demonstrated the ability of the ordinary artisan to successfully encapsulate mRNA in lipid nanoparticles.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Further, replacing a sequence with another has long been done in the molecular biology art and would be routine. One would be motivated to replace the furin sequence because Fang teaches that constructs may be designed with various furin sequences, and that since carboxypeptidases (CPs) are able to remove basic amino acid residues at the C-terminus of a protein, all amino acid resides derived from a furin cleavage site which contain exclusively basic amino acids R or K can be removed by a CP (col 15, lines 12-42).
Claim(s) 19, 20, 37, and 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Precigen as applied to claims 1, 2, 4, 5, 14-17, 23, and 34-36 above, and further in view of Black (US 2013/0011903, published 1/10/2013).
Regarding Claims 19, 20, 37, and 38, Precigen does not teach the nucleic acid construct further comprises a polynucleotide sequence encoding a thymidine kinase, nor the thymidine kinase being in a mutated form with increased cell kill activity relative to a wild-type thymidine kinase.
Black teaches a nucleic acid construct comprising a polynucleotide sequence encoding a thymidine kinase (TK), and thymidine kinase being in a mutated form with increased cell kill activity relative to a wild-type thymidine kinase [0018].
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the recombinant retroviral vector of Precigen to include a mutant TK-encoding nucleic acid sequence as taught by Black and yield predictable results. Black teaches that the in addition to thymidine kinase, vectors taught by Black may include IL-12 [0111]. Additionally, both retroviral vectors taught by Precigen and Black are used for gene therapy [0008]. Therefore, an artisan could add TK (or mutated TK) to the vector taught by Precigen with a reasonable expectation of success
One would be motivated to make this modification because as taught by Black, TK and TK mutants may be utilized therapeutically by introducing a retroviral vector which expresses the protein into the cell, followed by administration of a nucleoside analogue such as acyclovir or ganciclovir. HSVTK-1 then phosphorylates the nucleoside analogue, creating a toxic product capable of killing the host cell. Thus, use of retroviral vectors which express HSVTK has been suggested for not only the treatment of cancers, but for other diseases as well [0009].
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 19, 23, and 34-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 28, 29, and 37 of U.S. Patent No. 12234475 to Chung. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent discloses the same vector as the instant case.
Regarding instant case claims 1, 34, and 35, patent claim 1 teaches a method of treating cancer in a subject, comprising administering to the subject a first murine leukemia virus recombinant retroviral vector comprising a nuclei