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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 20, 2026 has been entered.
Detailed Action
This action is in response to papers filed April 20, 2026.
Amendments
Applicant's response and amendments, filed February 19, 2026 and April 20, 2026, to the prior Office Action are acknowledged. Applicant has cancelled Claims 5-9, 12-13, and 22, amended Claims 1-2, 4, and 21, and withdrawn Claims 14-20, and added new claims, Claim 23.
Claims 1-4, 10-11, 14-21, and 23 are pending.
The amendment to the claims filed on April 20, 2026 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The After-Final claim set filed on February 19, 2026 was not entered.
(1) Claim listing.
The correct status of Claims 1-2 and 21 is (Currently amended).
The correct status of Claim 23 is (New).
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as "withdrawn- currently amended."
Claims 1-2 and 21 fail to provide the required markings.
Election/Restriction
Applicants’ election without traverse of Group I, e.g., Claims 1-13 and 21, was previously acknowledged.
Claims 1-4, 10-11, 14-21, and 23 are pending.
Claims 14-20 were previously withdrawn from consideration by the examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. The restriction requirement was previously made Final.
Claims 1-4, 10-11, 21, and 23 are currently under examination.
Priority
This application is a CON of U.S. Application 15/441,545 filed on 02/24/2017, now U.S. Patent 10,344,067, which claims the benefit under 35 U.S.C. 119(e) of prior-filed provisional application 62/299,788, filing date 02/25/2016.
Thus, the earliest possible priority for the instant application is February 25, 2016.
Terminal Disclaimer
1. The terminal disclaimer filed on August 5, 2024 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of the full statutory term of U.S. Patent No. 10,344,067 has been reviewed and is accepted. The terminal disclaimer has been recorded.
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.
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.
2. Claims 21 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 21 and 23 recite the phrase “the amino acid sequence as set forth in SEQ ID NO…”).
As a first matter, the phrase "as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is the Examiner’s position that the use of the term “as” renders the SEQ ID NO as an example [emphasis added] and does not exclude other amino acid sequences. Neither the claims nor the specification disclose what amino acid sequences are objectively included and/or excluded by “as set forth in”.
As a second matter, the claims recite the phrases “the…sequence set forth in”, which renders the claims indefinite because the reference SEQ ID NO’s are each composed of a plurality of amino acid sequences or subsequences, and it is unclear to which sequence or subsequence “set forth in” the reference SEQ ID NO Applicant refers.
The preposition “in”, per “set forth in” does not have the same meaning as the preposition “of”. For example, “in” indicates a location or position within a limit or reference, e.g. a fragment or some portion of the referenced SEQ ID NO.
The house is in Tippecanoe county.
PNG
media_image1.png
120
235
media_image1.png
Greyscale
Three cows are grazing in the field.
PNG
media_image2.png
113
291
media_image2.png
Greyscale
The preposition “of” indicates possession of the reference, characteristic, or trait, that is to say, the entirety of the referenced SEQ ID NO.
As a third matter, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recite the broad recitation “as set forth in SEQ ID NO”, and the claim also recites “SEQ ID NO:10 or 12” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
As a fourth matter, the phrase “the amino acid sequence as set forth in SEQ ID NO…”, which renders the claim indefinite because the referenced SEQ ID NO is composed of a plurality of amino acid subsequences, respectively.
The Directors Technology Center 1600 Memorandum, Nucleic Acid and Peptide Claim Interpretation: “A” and “The” (December 29, 2005) informs the TC1600 Examiners that the phrase “A nucleic acid comprising a nucleotide sequence of SEQ ID NO:1” encompasses nucleic acids that comprise any portion of SEQ ID NO:1; whereas, the phrase “A nucleic acid comprising the nucleotide sequence of SEQ ID NO:1” is directed only to nucleic acids that comprise the full length of SEQ ID NO:1.
English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
To the extent that Applicant is requiring the entirety of the referenced SEQ ID NO, then replacing the phrases “the… sequence as set forth in” with the phrase “the… sequence of SEQ ID NO:” would render the rejection moot.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
The Examiner suggests amending the claims cancelling recitation of “as set forth in”, and instead recite “the… sequence of SEQ ID NO:”.
See, for example, prior Claim 13 (claim set filed March 12, 2025, “the…sequence of SEQ ID NO”.
3. Claims 1-4, 10-11, 21, and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicant has amended Claim 1 to recite a mouse p35 subunit, a mouse p40 subunit, a human p35 subunit, and a human p40 subunit.
Claim 2 recites a “human” p35 and p40 subunit.
The terms “human” and “mouse” in Claims 1-2 is/are relative terms which renders the claims indefinite. The terms “human” and “mouse” is/are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
As discussed in the prior Office Action (see also 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection below), [047] discloses wherein the variant includes muteins, one or more amino acid substitutions, deletions, or additions, including protein fragments, said variant need only be at least 50% identical to a reference IL-12 polypeptide, and “having the indicated activity”, for which there is no specific “indicated activity” but for some biological activity disclosed at a high level of generality.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that are identified to be “human”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-human”, for example.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that that are identified to be “mouse”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-mouse”, for example.
GenBank KAL4683417.1 (2025) teaches an IL-12beta subunit amino acid sequence from non-human primates that is 98% identical to human IL-12beta subunit, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “human”, but not mouse, canine, cow, sheep, pig, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “mouse”, but not human, canine, cow, sheep, pig, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “pig”, but not human, canine, cow, sheep, mouse, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, what amino acids of an IL-12 p35 subunit must be present so as to objectively identify it as being “human”, as opposed to what amino acids may be modified, e.g. deleted, substituted, or additionally inserted, yet objectively remain being “human”, for example.
The claims fail to recite, and the specification fails to disclose, what amino acids of an IL-12 p35 subunit must be present so as to objectively identify it as being “mouse”, as opposed to what amino acids may be modified, e.g. deleted, substituted, or additionally inserted, yet objectively remain being “mouse”, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first IL-12 p35 subunit amino acid sequence that is objectively not a “human”, or “mouse”, IL-12 p35 subunit sequence, respectively, into a second IL-12 p35 subunit amino acid sequence that is now objectively a “human”, or “mouse”, IL-12 p35 subunit sequence, respectively, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “mouse”, but not human, canine, cow, sheep, pig, horse, non-human primate, etc…
Rather, the genus of IL-12 p35 and p40 subunit variants, respectively, encompassed by the claims which are/are not “human” and/or “mouse” is considered an arbitrary and subjective determination.
While it is clear that dependent Claims 21 and 23 recite SEQ ID NO:12, the claims do not make up for the deficiencies of the independent claim. See discussion in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
The Examiner suggests amending the independent claim to recite, e.g.:
‘an expressible polynucleotide comprising the sequence of SEQ ID NO:12 encoding a fusion polypeptide comprising IL-12 p35 and p40 subunits’.
4. Claim(s) 1-4, 10-11, 21, and 23 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.
Claim 1 has been amended to recite the recombinant virus encoding an IL-12 fusion protein further comprises a nucleic acid encoding a soluble anti-PD-L1 antibody,
wherein said p35 subunit and said p40 subunit of said fusion polypeptide are a mouse p35 subunit and a mouse p40 subunit, or a human p35 subunit and a human p40 subunit.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
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).
[047] discloses wherein the variant includes muteins, one or more amino acid substitutions, deletions, or additions, including protein fragments, said variant need only be at least 50% identical to a reference IL-12 polypeptide, and “having the indicated activity”, for which there is no specific “indicated activity” but for some biological activity disclosed at a high level of generality.
GenBank NP_000873.2 (human IL-12 subunit alpha; 2024; of record) teaches that the IL-12 alpha subunit is about 253 amino acids in length.
GenBank NP_002178.2 (human IL-12 subunit beta; 2025; of record) teaches that the IL-12 beta subunit is about 328 amino acids in length.
Thus, the breadth of Claims 1 and 21 reasonably encompasses IL-12 fusion proteins comprising about 580 amino acids.
In light of the specification disclosing that the variants need only be 50% identical to a reference IL-12 protein, the breadth of the claims reasonably encompasses as many as 290 amino acid substitutions, insertions, or deletions.
20^290 is an infinite number of structurally and functionally undisclosed IL-12 fusion protein variants.
Even if one considered variants having at least 95% identity to a reference IL-12 protein, the breadth of the claims reasonably encompasses as many as 29 amino acid substitutions, insertions, or deletions.
20^29 = about 5x10^37 structurally and functionally undisclosed IL-12 fusion protein variants.
(https://www.calculator.net/exponent-calculator.html; last visited March 12, 2025; of record)
Claim 21 fails to recite, and the specification fails to disclose, an IL-12 fusion protein variant that is objectively a “mouse IL-12”, as opposed to a non-mouse IL-12, as opposed to a “human IL-12”, as opposed to a non-human IL-12, as opposed to a non-human, non-mouse IL-12.
The claims fail to recite, and the specification fails to disclose, what amino acids are required to be present in the IL-12 fusion protein so as to objectively identify it as being a “mouse” IL-12 fusion protein, as opposed to a non-mouse IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids may be absent in the IL-12 fusion protein so as to objectively identify it as being a “mouse” IL-12 fusion protein, as opposed to a non-mouse IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids are required to be present in the IL-12 fusion protein so as to objectively identify it as being a “human” IL-12 fusion protein, as opposed to a non-human IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids may be absent in the IL-12 fusion protein so as to objectively identify it as being a “human” IL-12 fusion protein, as opposed to a non-human IL-12 fusion protein.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007; of record) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006; of record) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast, to wit, infinite, genus of structurally undisclosed IL-12 fusion protein variants, and wherein the infinite genus of structurally undisclosed IL-12 fusion proteins will necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, infinite genus of structurally undisclosed IL-12 fusion protein variants, and wherein the infinite genus of structurally undisclosed IL-12 fusion proteins will necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention. While applicant has demonstrated this with regard to the specific IL-12 fusion polypeptide encoded by the measles virus expression vectors comprising the sequence of SEQ ID NOs: 4, 5, 6, 7, 14, and 15, per se, possession has not been demonstrated for the infinite genus of about structurally and functionally undisclosed IL-12 fusion protein variants.
The claims fail to recite, and the specification fails to disclose, a first IL-12 variant of the infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants that necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer, as opposed to a second IL-12 variant of the infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants that does not necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first IL-12 variant of the infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants that does not possess some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer into a second IL-12 variant of the infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants that now necessarily and predictably has some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that are identified to be “human”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-human”, for example.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that that are identified to be “mouse”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-mouse”, for example.
GenBank KAL4683417.1 (2025) teaches an IL-12beta subunit amino acid sequence from non-human primates that is 98% identical to human IL-12beta subunit, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “human”, but not mouse, canine, cow, sheep, pig, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “mouse”, but not human, canine, cow, sheep, pig, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “pig”, but not human, canine, cow, sheep, mouse, horse, non-human primate, etc…
The claims fail to recite, and the specification fails to disclose, what amino acids of an IL-12 p35 subunit must be present so as to objectively identify it as being “human”, as opposed to what amino acids may be modified, e.g. deleted, substituted, or additionally inserted, yet objectively remain being “human”, for example.
The claims fail to recite, and the specification fails to disclose, what amino acids of an IL-12 p35 subunit must be present so as to objectively identify it as being “mouse”, as opposed to what amino acids may be modified, e.g. deleted, substituted, or additionally inserted, yet objectively remain being “mouse”, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first IL-12 p35 subunit amino acid sequence that is objectively not a “human”, or “mouse”, IL-12 p35 subunit sequence, respectively, into a second IL-12 p35 subunit amino acid sequence that is now objectively a “human”, or “mouse”, IL-12 p35 subunit sequence, respectively, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “mouse”, but not human, canine, cow, sheep, pig, horse, non-human primate, etc…
Rather, the genus of IL-12 p35 and p40 subunit variants, respectively, encompassed by the claims which are/are not “human” and/or “mouse” is considered an arbitrary and subjective determination.
While it is clear that dependent Claims 21 and 23 recite SEQ ID NO:12, the claims do not make up for the deficiencies of the independent claim. See discussions in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
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).
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’).
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 initial IL-12 amino acid sequence may be the art-recognized human or mouse IL-12 polypeptide does not tell you anything at all about the structure (amino acid sequences) of the infinite and/or enormously vast genus of about 5x10^37 structurally and functionally undisclosed human and non-human IL-12 variants that necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
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 claims encompass an infinite and/or enormously vast genus of about 5x10^37 structurally and functionally undisclosed human and non-human IL-12 variants that necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity, for which there is no objective evidence that said infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to the measles virus expression vectors comprising the sequence of SEQ ID NOs: 4, 5, 6, 7, 14, and 15, and the IL-12 fusion polypeptide encoded therein.
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 correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that the amendment to independent Claim 1 renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. The amendment does nothing to render the prior rejection moot. See also the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
Applicant argues that the claims are not drawn to IL-12 variants.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant is factually incorrect. The claimed “human” and “mouse” p35 and p40 subunits are recited at a high level of generality. [047] discloses wherein the variant includes muteins, one or more amino acid substitutions, deletions, or additions, including protein fragments, said variant need only be at least 50% identical to a reference IL-12 polypeptide, and “having the indicated activity”, for which there is no specific “indicated activity” but for some biological activity disclosed at a high level of generality.
Thus, the breadth of the claims encompasses an infinite and/or enormously vast genus of about 5x10^37 structurally and functionally undisclosed human and non-human IL-12 variants that necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity, for which there is no objective evidence that said infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer (intended use of the claimed recombinant virus, e.g. [002], “especially for the treatment or prevention of a human disease”).
Applicant argues that the ordinary artisan could readily differentiate between a human or non-human IL-12, or between a murine or non-murine IL-12.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that are identified to be “human”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-human”, for example.
The claims and specification denote that there is a first subgenus of IL-12 p35 subunit amino acid variants that that are identified to be “mouse”, as opposed to a second subgenus of IL-12 p35 subunit amino acid variants that are identified to be “non-mouse”, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “human”, but not mouse, canine, cow, sheep, pig, horse, non-human primate, etc…, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “mouse”, but not human, canine, cow, sheep, pig, horse, non-human primate, etc…, for example.
The claims fail to recite, and the specification fails to disclose, the amino acid sequence of an IL-12 p35 subunit, including variants having as little as 50% identity thereto, that objectively identifies it as being “pig”, but not human, canine, cow, sheep, mouse, horse, non-human primate, etc…, for example.
Applicant argues that cancellation of the phrases “for stimulating an immune response of a subject” and/or “a variant thereof” renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s amendments and argument do nothing to satisfy the substantive issues that the claims encompass an infinite and/or enormously vast genus of about 5x10^37 structurally and functionally undisclosed human and non-human IL-12 variants.
The specification discloses [047] that the variants need only be 50% identical to a reference IL-12 protein.
The claims fail to recite, and the specification fails to disclose, what amino acids are required to be present in the IL-12 fusion protein so as to objectively identify it as being a “mouse” IL-12 fusion protein, as opposed to a non-mouse IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids may be absent in the IL-12 fusion protein so as to objectively identify it as being a “mouse” IL-12 fusion protein, as opposed to a non-mouse IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids are required to be present in the IL-12 fusion protein so as to objectively identify it as being a “human” IL-12 fusion protein, as opposed to a non-human IL-12 fusion protein.
The claims fail to recite, and the specification fails to disclose, what amino acids may be absent in the IL-12 fusion protein so as to objectively identify it as being a “human” IL-12 fusion protein, as opposed to a non-human IL-12 fusion protein.
Applicant’s working examples are directed to the measles virus expression vectors comprising the sequence of SEQ ID NOs: 4, 5, 6, 7, 14, and 15, and the IL-12 fusion polypeptide encoded therein.
Instant independent Claim 1 is vastly broader in scope than Applicant’s SEQ ID NOs: 4, 5, 6, 7, 14, and 15.
5. Claim(s) 1-4, 10-11, 21, and 23 are 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 the measles virus expression vectors comprising the sequence of SEQ ID NOs: 4, 5, 6, 7, 14, and 15, does not reasonably provide enablement for an infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants that necessarily and predictably have some unrecited and undisclosed functional property of some amount of unrecited and undisclosed biological activity, for which there is no objective evidence that said infinite genus of structurally and functionally undisclosed human and non-human IL-12 variants will necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the treatment of cancer.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for enablement 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 correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 103
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 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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
6. Claims 1-3, 10-11, 21, and 23 are rejected under 35 U.S.C. 103(a) as being unpatentable over Medin et al., (US Pub 2014/0370039; of record) in view of Hoffman et al (2003, J Infect Dis 188:1553-1561; of record IDS filed on 8/28/2017) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record).
Regarding Claim 1, Medin et al disclosed a recombinant virus including Lentiviral vectors (LVs) comprising a polynucleotide gene comprising a construct encoding a bioactive form of IL-12 which is a heterodimer comprised of two subunits, p35 and p40, both of which are required for the secretion of the active form of IL-12, p70 (paragraphs [0005][0008][0092]). Medin et al disclosed that Interleukin-12 acts on dendritic cells (DC), leading to increased maturation and antigen presentation, which can allow for the initiation of a T cell response to tumor specific antigens. It also drives the secretion of IL-12 by DCs, creating a positive feedback mechanism to amplify the immune response (paragraphs [0008] [0094] [0101][1036]). Medin disclosed methods of inducing or enhancing an immune response in a subject comprising administering to a subject an isolated virus, transduced cell, population of cells or composition comprising a vector construct that encodes and secretes IL-12 (paragraphs [0019]-[0021]). Moreover, Medin et al disclosed at paragraph [0096]):
“one embodiment the polynucleotide comprises the sequence of both IL-12 subunits, p35 and p40, separated by an IRES sequence which permits expression of multiple transgenes from a single transcript. In other embodiments, the polynucleotide directs expression of an IL-12 fusion polypeptide that retains IL-12 activity. In one embodiment, the polynucleotide that directs the expression of IL-12 comprises a cDNA encoding a human IL-12 polypeptide fusion obtained from InVivoGen (pORF with IL-12elasti(p40::p35)).” [emphasis added]
Medin et al do not disclose or suggest a recombinant virus of the family Paramyxoviridae.
However, prior to the effective filing date of the instantly claimed invention, Hoffman et al taught cloning and expression of IL-12 into Measles virus (MV), including cloning of each p40-p35 subunits of IL-12 separated by IRES (see abstract and Figure 1).
Medin et al disclosed immune modulatory cassettes comprising polynucleotides that direct expression of a molecule or polypeptide that enhance the anti-tumor activity of IL-12 transduced cells including cytokines. For example, antagonists of IL-10, which inhibit IL-12 (paragraphs [0077]- [0078]).
Medin et al disclosed secretion of IL-12 at a threshold level (paragraph [0012]) and "immune modulatory cassette" comprising a polynucleotide that directs expression of a molecule or polypeptide that enhances the anti-tumor effect of an IL-12 transduced cell (paragraph [0077]). Additionally, Medin et al disclosed antibodies and their fragments including scFv, dsFv, ds-scFv, dimers, minibodies (paragraph [0062]) and monoclonal antibody therapy (paragraphs [0062][0070]), such that one of ordinary skill in the art would have cloned a secreted immunoglobulin as the immune regulatory molecule further enhancing the anti-tumor activity of IL-12 transduced cells, including well-known and routine used fragments of immunoglobulins such as IgG1-Fc able to interact with Fc receptors on the surface of various immune cells.
Neither Medin et al nor Hoffman et al teach/disclose wherein the viral vector comprises a nucleic acid encoding a secreted, soluble anti-PD-L1 antibody.
However, prior to the effective filing date of the instantly claimed invention, Nolin et al disclosed oncolytic viruses genetically modified to encode a PD-1 binding protein, such as an anti-PD-1 antibody or more specifically an anti-PD-1 single chain antibody, or a protein which antagonizes the activity of PD-1, such as and anti-PD-L1 and/or anti-PD-L2 antibody (e.g. [0006-7, 47]), and where the virus is a measles virus, Sindbis viruses, and influenza viruses (e.g. [0008, 40]; claim 4). Nolin et al disclosed that recombinant vectors can also encode a signal peptide to direct the secretion of extracellular antibody fragments (e.g. [0077]), wherein said soluble anti-PD-L1 antibodies would necessarily have a signal peptide in order to be secreted (e.g. [0077]).
Nolin et al disclosed that the oncolytic virus encoding the PD-1 binding agent can be combined with additional anti-cancer agents and therapies, such as chemotherapy, radiotherapy, immunotherapy, and other biological interventions (e.g. [0125]).
Nolin et al disclosed the viral expression vector may further comprise a gene encoding an immuno-modulatory protein, e.g. IL-12 (e.g. [0011, 91]).
Thus, Nolin et al disclosed the scientific and technical concepts of expressing an IL-12 transgene in combination with an anti-PD-L1 antibody from an oncolytic viral vector, including a measles viral vector.
Regarding Claims 1-2, Medin disclosed that the p35 subunit and a p40 subunit of an IL-12 is a human IL-12 or murine IL-2 (paragraph [0095]).
Hoffmann et al taught that the p35 subunit and p40 subunit of an IL-12 is a human IL-12 (e.g. pg 1554, col. 1, Methods, Virus, “human IL-12”).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have prima facie obvious to for one of ordinary skill in the art to substitute a first viral vector encoding and expressing IL-12, to wit, the lentiviral vector of Medin et al, with a second viral vector encoding and expressing IL-12, to wit, the measle’s virus vector Hoffman et al’s with 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).” 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. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). A skilled artisan would have had a reasonable expectation of success as controlling gene vector expression using Measles virus to express p40 and p35 IL-12 subunits under the control of the same promoter to drive translation of the downstream encoded protein was well-known in the art before the effective filing date of the claimed invention.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a transgene encoding a molecule that inhibits IL-12 down modulation, as disclosed by Medin et al, with a transgene encoding an agent that inhibits the binding of PD-1 ligands to the receptor, e.g. an anti-PD-L1 antibody, thereby co-expressing IL-12 with an anti-PD-L1 antibody from a measles viral expression vector, with 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. Nolin et al disclosed the scientific and technical concepts of expressing an IL-12 transgene in combination with an anti-PD-L1 antibody from an oncolytic viral vector, including a measles viral vector.
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).
Regarding Claim 3, Medin et al disclosed a functional assembled IL-12p35 and IL-12p40 heterodimer comprising an elastin linker, see pages 42-44 for SEQ ID NO:5, the elastin linker sequence being underlined. Thus, Medin disclosed a polynucleotide that directs the expression of IL-12 comprises a cDNA encoding a human IL-polypeptide fusion obtained from InVivoGen (pORF with IL-12elasti (p40::p350)) (TABLE-US-00003 [0435] Sequences ).
With respect to Claims 21 and 23, Medin et al disclosed a human IL-12 coding sequence (SEQ ID NO:4) which encodes one or more amino acid sequences (lower line) set forth in SEQ ID NO:12 (upper line), as shown below:
MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITW
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITW
TLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ
KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV
RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPNN
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |
RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKN
LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
RKNASISVRAQDRYYSSSWSEWASVPCS----GGGGGGSRNLPVATPDPGMFPCLHHSQN
|||||||||||||||||||||||||||| | | |:|||||||||||||||||||||
RKNASISVRAQDRYYSSSWSEWASVPCSVPGVGVPGVGARNLPVATPDPGMFPCLHHSQN
LLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETS
FITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVI
||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
FITNGSCLASRKTSFMMALCLSSIYEDSKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVI
DELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
With respect to Claims 10-11, Hoffmann et al taught wherein the measles virus vector is a recombinant Edmonston B virus (e.g. pg 1554, col. 1, Methods, Virus, “Edmonton B”), whereby Edmonston B measles virus is an art-recognized species of Measles Morbillivirus.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the Examiner has exercised impermissible hindsight.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Medin et al clearly disclosed a plurality of different viral expression vectors with which to express IL-12 (e.g. [0098]).
Hoffman et al successfully demonstrated the ability to express human IL-12 from a recombinant measles virus vector (e.g. Title, “a Recombinant Measles Virus Expressing Interleukin-12…”).
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
Those of ordinary skill in the art have long-recognized that viral expression vectors are substitutable, as evidenced by Medin et al.
Thus, the simple substitution of one known element for another, to wit, substitute lentiviral vector for measles vector to express IL-12, 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).” 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.
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).
Medin et al disclosed the scientific and technical concept of expressing IL-12 along with an immune modulatory cassette from the viral expression vector,
Nolin et al disclosed the viral expression vector expressing an anti-PD-L1 antibody may further comprise a gene encoding an immuno-modulatory protein, e.g. IL-12 (e.g. [0011, 91]).
Thus, Nolin et al disclosed the scientific and technical concepts of expressing an IL-12 transgene in combination with an anti-PD-L1 antibody from an oncolytic viral vector, including a measles viral vector.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
Those of ordinary skill in the art have long-recognized that immune-modulatory transgenes are substitutable, as evidenced by Nolin et al (e.g. [0011] and/or [0091]).
Thus, the simple substitution of one known element for another, to wit, substitute a molecule that inhibits IL-12 downregulation for an anti-PD-L1 antibody, thereby co-expressing IL-12 with an anti-PD-L1 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).” 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. Nolin et al explicitly disclosed the viral vector, including measles viral vector, may co-express IL-12 with PD-1 binding agent that antagonizes the binding of PD-1 ligands to the receptor, e.g. anti-PD-L1 antibodies.
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).
Applicant argues that none of the cited references teach that expression of IL-12 and anti-PD-L1 from a single oncolytic vector is safe, predictable, or yields no more than predictable results.
Applicant’s argument(s) has been fully considered, but is not persuasive. All that is required by the claims is that the Paramyxovirus, Morbillivirus, or more specifically, measles Edmonston B strain virus, express both IL-12 and anti-PD-L1.
There is no safety requirement.
Applicant has provided no objective evidence to contradict that which has already been successfully reduced to practice in the art, to wit, expression of IL-12 from an Edmonston B strain virus (Nolin et al).
The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
All that is required to make the instantly claimed recombinant viral vector is art-recognized molecular biology techniques and reagents, commercially available and routinely used for many decades (molecular biology is technology that has been around since the 1980’s).
Thus, no undue experimentation is required.
It is not required in this analysis that the expectation of success be a certainty; only one that is reasonable to a person of ordinary skill. See In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness”).
As evidenced by Blechacz et al (Measles Virus as an Oncolytic Vector Platform, Current Gene Therapy 8(3): 162-175, 2008; of record), those of ordinary skill in the art previously successfully reduced to practice the ability to synthesize and express two heterologous proteins from a recombinant measles virus (e.g. pg 171, col. 1, MV-PNP-CEA).
Thus, here too, Applicant has provided no objective evidence to contradict that which has already been successfully reduced to practice in the art.
Applicant argues that a PD-L1 blockade cannot replace IL-10 blockade because the two molecules act on different sides of the IL-12 signaling cascade.
Applicant’s argument(s) has been fully considered, but is not persuasive. It is not required that all immuno-modulatory transgenes to be combined with IL-12 expression act only in the same side of the IL-12 signaling cascade as IL-10 blockade, per Applicant’s argument.
Nolin et al explicitly disclosed the viral vector, including measles viral vector, may co-express IL-12 with PD-1 binding agent that antagonizes the binding of PD-1 ligands to the receptor, e.g. anti-PD-L1 antibodies.
7. Claim 4 is rejected under 35 U.S.C. 103(a) as being unpatentable over Medin et al., (US Pub 2014/0370039; of record) in view of Hoffman et al (2003; of record IDS filed on 8/28/2017) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record), as applied to Claims 1-3, 10-11, 21, and 23 above, and in further view of Brinkmann et al., (US Pub 2010/0081796; of record) for the reasons already of record as stated at pages 10-12 of the office action filed on 7/2/2021.
8. Claims 10-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over Medin et al., (US Pub 2014/0370039; of record) in view of Hoffman et al (2003; of record IDS filed on 8/28/2017) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record), as applied to Claims 1-3, 10-11, 21, and 23 above, and in further view of Combredet et al. (2003; J. Virol., pp. 11546-11554; of record) for the reasons already of record as stated at pages 13-14 of the office action filed on 7/2/2021.
Applicants have not submitted new arguments to rebut rejection of claim 4 under 35 USC § 103 made in the Office Action of 7/2/2021. The examiner refers applicants to the reasons of record and the reasons set forth in the paragraphs above.
9. Claims 1-3, 10, 21, and 23 are rejected under 35 U.S.C. 103(a) as being unpatentable over Singh et al (A recombinant measles virus expressing biologically active human interleukin-12, J. General Virology 80(1): 101-106, 1999; of record) in view of Medin et al (2014/0370039; of record) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record).
Singh et al is considered relevant prior art for having taught a recombinant measles virus vector expressing human IL-12 (p35-IRES-p40) (e.g. Abstract; Figure 1).
Sing et al taught wherein the measles virus is a well-suited vector for delivery of proteins of immunogenic and therapeutic importance (Abstract).
Singh et al differ from the instant claims in that the IL-12 polypeptide is not a p35-p40 fusion polypeptide.
However, prior to the effective filing date of the instantly claimed invention, Medin et al is considered relevant prior art for having disclosed viral vectors encoding IL-12, wherein the polynucleotide encoding IL-12 may encode IL-12 p35-IRES-p40 [0096], as per Singh et al, or an IL-12 fusion protein [0096].
Medin et al disclosed immune modulatory cassettes comprising polynucleotides that direct expression of a molecule or polypeptide that enhance the anti-tumor activity of IL-12 transduced cells including cytokines. For example, antagonists of IL-10, which inhibit IL-12 (paragraphs [0077]- [0078]).
Medin et al disclosed secretion of IL-12 at a threshold level (paragraph [0012]) and "immune modulatory cassette" comprising a polynucleotide that directs expression of a molecule or polypeptide that enhances the anti-tumor effect of an IL-12 transduced cell (paragraph [0077]). Additionally, Medin et al disclosed antibodies and their fragments including scFv, dsFv, ds-scFv, dimers, minibodies (paragraph [0062]) and monoclonal antibody therapy (paragraphs [0062][0070]), such that one of ordinary skill in the art would have cloned a secreted immunoglobulin as the immune regulatory molecule further enhancing the anti-tumor activity of IL-12 transduced cells, including well-known and routine used fragments of immunoglobulins such as IgG1-Fc able to interact with Fc receptors on the surface of various immune cells.
Regarding Claims 1-2, Singh et al taught wherein the p35 subunit and p40 subunit of an IL-12 is a human IL-12 (e.g. Title, “human interleukin-12”).
Medin disclosed that the p35 subunit and p40 subunit of an IL-12 is a human IL-12 or murine IL-2 (paragraph [0095]).
Neither Singh et al nor Medin et al teach/disclose wherein the viral vector comprises a nucleic acid encoding a secreted, soluble anti-PD-L1 antibody.
Nolin et al disclosed oncolytic viruses genetically modified to encode a PD-1 binding protein, such as an anti-PD-1 antibody or more specifically an anti-PD-1 single chain antibody, or a protein which antagonizes the activity of PD-1, such as and anti-PD-L1 and/or anti-PD-L2 antibody (e.g. [0006-7, 47]), and where the virus is a measles virus, Sindbis viruses, and influenza viruses (e.g. [0008, 40]; claim 4). Nolin et al disclosed that recombinant vectors can also encode a signal peptide to direct the secretion of extracellular antibody fragments (e.g. [0077]), wherein said soluble anti-PD-L1 antibodies would necessarily have a signal peptide in order to be secreted (e.g. [0077]).
Nolin et al disclosed that the oncolytic virus encoding the PD-1 binding agent can be combined with additional anti-cancer agents and therapies, such as chemotherapy, radiotherapy, immunotherapy, and other biological interventions (e.g. [0125]).
Nolin et al disclosed the viral expression vector may further comprise a gene encoding an immuno-modulatory protein, e.g. IL-12 (e.g. [0011, 91]).
Thus, Nolin et al disclosed the scientific and technical concepts of expressing an IL-12 transgene in combination with an anti-PD-L1 antibody from an oncolytic viral vector, including a measles viral vector.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first polynucleotide encoding human IL-12 p35-IRES-p40, as taught by Singh et al, with a second polynucleotide encoding a human IL-12 fusion protein, as disclosed by Medin et al, in a recombinant measles virus expression vector with 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 a first polynucleotide encoding human IL-12 p35-IRES-p40 with a second polynucleotide encoding a human IL-12 fusion protein in a recombinant measles virus expression vector because Medin et al disclose the polynucleotide encoding human IL-12 may either encode p35-IRES-p40, as per Singh et al, or a fusion protein [0096].
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a transgene encoding a molecule that inhibits IL-12 down modulation, as disclosed by Medin et al, with a transgene encoding an agent that inhibits the binding of PD-1 ligands to the receptor, e.g. an anti-PD-L1 antibody, thereby co-expressing IL-12 with an anti-PD-L1 antibody from a measles viral expression vector, with 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. Nolin et al disclosed the scientific and technical concepts of expressing an IL-12 transgene in combination with an anti-PD-L1 antibody from an oncolytic viral vector, including a measles viral vector.
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).
Regarding Claim 3, Medin et al disclosed a functional assembled IL-12p35 and IL-12p40 heterodimer comprising an elastin linker, see pages 42-44 for SEQ ID NO:5, the elastin linker sequence being underlined. Thus, Medin et al disclosed a polynucleotide that directs the expression of IL-12 comprises a cDNA encoding a human IL-polypeptide fusion obtained from InVivoGen (pORF with IL-12elasti (p40::p350)) (TABLE-US-00003 [0435] Sequences ).
With respect to Claim 10, Singh et al taught the recombinant virus is a measles virus.
As evidenced by Combredet et al (2003; of record), measles virus is an art-recognized Morbillivirus (e.g. pg 11546, col. 2). See also Blechacz et al (e.g. pg 162, col. 2).
With respect to Claims 21 and 23, Medin et al disclosed a human IL-12 coding sequence (SEQ ID NO:4) which encodes one or more amino acid sequences (lower line) set forth in SEQ ID NO:12 (upper line), as shown below:
MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITW
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITW
TLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ
KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV
RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPNN
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |
RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKN
LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
RKNASISVRAQDRYYSSSWSEWASVPCS----GGGGGGSRNLPVATPDPGMFPCLHHSQN
|||||||||||||||||||||||||||| | | |:|||||||||||||||||||||
RKNASISVRAQDRYYSSSWSEWASVPCSVPGVGVPGVGARNLPVATPDPGMFPCLHHSQN
LLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETS
FITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVI
||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
FITNGSCLASRKTSFMMALCLSSIYEDSKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVI
DELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Applicant did not contest the teachings of Medin et al and Nolan et al as applied to the obviousness to substitute the soluble anti-PD-L1 antibody of Nolan et al for the antagonists of IL-10, which inhibit IL-12, of Medin et al with a reasonable expectation of success.
10. Claim 4 is rejected under 35 U.S.C. 103(a) as being unpatentable over Singh et al (A recombinant measles virus expressing biologically active human interleukin-12, J. General Virology 80(1): 101-106, 1999; of record) in view of Medin et al (2014/0370039; of record) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record), as applied to Claims 1-3, 10, and 21, and 23 above, and in further view of Brinkmann et al (US Pub 2010/0081796; of record) for the reasons already of record as stated at pages 10-12 of the office action filed on 7/2/2021.
Applicant did not contest the teachings of Medin et al and Brinkmann et al as applied to the obviousness to substitute the (glycine 4-serine)n linker of Brinkmann for the elastin linker of Medin with a reasonable expectation of success.
11. Claims 10-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over Singh et al (A recombinant measles virus expressing biologically active human interleukin-12, J. General Virology 80(1): 101-106, 1999; of record) in view of Medin et al (2014/0370039; of record) and Nolin et al (U.S. Patent Application Publication 2015/0250837; effective filing date of 9/20/12; of record), as applied to Claims 1-3, 10, and 21, and 23 above, and in further view of Combredet et al. (2003; J. Virol., pp. 11546-11554; of record) for the reasons already of record as stated at pages 13-14 of the office action filed on 7/2/2021.
Applicant did not contest the teachings of Medin et al and Combredet et al as applied to the obviousness to select a measles virus Edmonston A or B strain as the type of recombinant measles virus, which is an art-recognized Morbillivirus, to encode an IL-12 fusion protein with a reasonable expectation of success.
Citation of Relevant Prior Art
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Blechacz et al (Measles Virus as an Oncolytic Vector Platform, Current Gene Therapy 8(3): 162-175, 2008; of record) is considered relevant prior art for having taught the use of measles virus vectors, including the Edmonston vaccine strain of measles virus, whose genomes comprise polynucleotides encoding therapeutic transgenes to be an optimal platform for oncolytic virotherapy of cancer (e.g. Abstract; see also Table 1 reductions to practice). Blechacz et al taught that measle virus is an art-recognized Morbillivirus (e.g. pg 162, col. 2).
Thus, prior to the effective filing date of the instantly claimed invention (2016), those of ordinary skill in the art had long-recognized the use of measles virus vectors to express a therapeutic transgene in methods of treating cancer.
Conclusion
13. Claims 1-4, 10-11, 21, and 23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights