Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed March 6, 2026.
Amendments
Applicant's response and amendments, filed March 6, 2026, to the prior Office Action is acknowledged.
Applicant has cancelled Claims 2-5, 14, and 16-17, amended Claims 1, 6, 9-11, 15, and 18, withdrawn Claims 7, 12, 19, and 21, and added new claims, Claims 22-23.
Claims 1, 6-13, 15, and 18-23 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative means by which EBAG9/RCAS1 activity is inhibited is RNA interference, as recited in Claims 5-6, 14-15, and 17-18 (gene-silencing RNA);
ii) the alternative disease/condition to be treated is Non-Hodgkin lymphoma, as recited in Claim 20; and
iii) the alternative antigen to which the transgenic antigen-targeting construct binds is BCMA, as recited in Claim 11.
Claims 1, 6-13, 15, and 18-23 are pending.
Claims 7, 12, 19 and 21 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 6, 8-11, 13, 15, 18, 20, and 22-23 are under consideration.
Priority
This application is a 371 of PCT/EP2020/058355 filed on March 25, 2020.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A certified copy of foreign priority EPO 19164822.9 filed on March 25, 2019, has been filed in the instant application.
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.
1. The prior rejection of Claims 6, 9-11, and 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to Claim 6 to recite the vector encodes the CAR, which the Examiner finds persuasive.
2. The prior rejection of Claims 1, 5-6, 8-11, 13-15, 17-18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to Claim 1 to recite the introduction of an RNA interfering molecule whose nucleotide sequence is 100% complementary to an EBAG9 mRNA transcript, which the Examiner finds persuasive.
3. The prior rejection of Claims 1, 8-11, 13-15, 17-18, and 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement, is withdrawn for reasons discussed above.
4. The prior rejection of Claims 5 and 17 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claims.
5. Claims 1, 6-13, 15, and 18-23 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.
As a first matter, the term “according to” in Claims 1, 15, and 22-23 is a relative term which renders the claim indefinite. The term “according to” is not defined by the claim, 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.
As a second 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, Claims 1, 15, and 22-23 recite the broad recitation “sequence according to”, and the claim also recites SEQ ID NO's: 1, 2, 3, 6, 55-62, which is/are 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.
Those of ordinary skill in the art immediately recognize that the phrase “according to” does not have the same meaning as the preposition “of”.
The phrase “according to” is broader in scope that the preposition “of”.
Neither the claims nor the specification disclose a definition for “according to”.
The claims denote that there is/are:
a first subgenus of EBAG9 mRNA transcripts whose sequences are neither identical to SEQ ID NO’s:3-6, nor “according to” SEQ ID NO’s:3-6, as opposed to
a second subgenus of EBAG9 mRNA transcripts whose sequences are not identical to SEQ ID NO’s:3-6, but are “according to” SEQ ID NO’s:3-6.
The claims denote that there is/are:
a first subgenus of RNA interfering sequences whose sequences are neither identical to SEQ ID NO’s:1-2 or 55-62, nor “according to” SEQ ID NO’s:1-2 or 55-62, as opposed to
a second subgenus of RNA interfering sequences whose sequences are not identical to SEQ ID NO’s:1-2 or 55-62, but are “according to” SEQ ID NO’s:1-2 or 55-62.
Thus, that which does/does not fall within “according to” is considered to be an arbitrary and subjective determination, rendering the claim(s) indefinite.
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 claims canceling recitation of “according to”, and instead recite ‘the sequence of SEQ ID NO’.
6. Claims 1, 6-13, 15, and 18-23 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 1 and 15 have been amended to recite the introduction of an RNA interfering sequence comprising 18-40 nucleotides that are 100% complementary to an EBAG9 mRNA transcript [structure] and results in at least 70% reduction of EBAG9 expression [function].
The claims are considered indefinite because they do not recite the required structure(s) and/or method step parameter(s), e.g. nucleotide sequences and their corresponding working concentrations, that achieve the recited functional limitation at least 70% reduction of EBAG9 expression.
The specification discloses that not all RNA interfering sequences that target EBAG9 yield at least 70% reduction of EBAG9 expression (e.g. pg 55, lines 16-17, “H19 did not effectuate EBAG9 protein downregulation”).
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).
See further discussion in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description below.
7. Claim(s) 1, 6-13, 15, and 18-23 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.
Claims 1 and 15 have been amended to recite the introduction of an RNA interfering sequence comprising 18-40 nucleotides that are 100% complementary to an EBAG9 mRNA transcript [structure] and results in at least 70% reduction of EBAG9 expression [function].
Claim 18 recites inhibition of EBAG9 activity is obtained by siRNA, shRNA, or miRNA.
Claims 22-23 recite wherein the RNA interfering sequence comprises a sequence according to SEQ ID NO’s: 1-2 or 55-62.
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).
Those of ordinary skill in the art immediately recognize that the phrase “according to” does not have the same meaning as the preposition “of”.
The phrase “according to” is broader in scope that the preposition “of”.
Neither the claims nor the specification disclose a definition for “according to”.
The claims denote that there is/are:
a first subgenus of EBAG9 mRNA transcripts whose sequences are neither identical to SEQ ID NO’s:3-6, nor “according to” SEQ ID NO’s:3-6, as opposed to
a second subgenus of EBAG9 mRNA transcripts whose sequences are not identical to SEQ ID NO’s:3-6, but are “according to” SEQ ID NO’s:3-6.
The claims denote that there is/are:
a first subgenus of RNA interfering sequences whose sequences are neither identical to SEQ ID NO’s:1-2 or 55-62, nor “according to” SEQ ID NO’s:1-2 or 55-62, as opposed to
a second subgenus of RNA interfering sequences whose sequences are not identical to SEQ ID NO’s:1-2 or 55-62, but are “according to” SEQ ID NO’s:1-2 or 55-62.
Thus, that which does/does not fall within “according to” is considered to be an arbitrary and subjective determination.
The claims do not recite the required structure(s) and/or method step parameter(s), e.g. nucleotide sequences and their corresponding working concentrations, that achieve the recited functional limitation at least 70% reduction of EBAG9 expression.
The specification discloses that not all RNA interfering sequences that target EBAG9 yield at least 70% reduction of EBAG9 expression (e.g. pg 55, lines 16-17, “H19 did not effectuate EBAG9 protein downregulation”).
The breadth of “at least 70% reduction” allows for embodiments that are not more than 70% reduced, not more than 73% reduced, not more than 76% reduced, not more than 79% reduced, etc…
The functional language “at least 70% reduced EBAG9 expression” is a result-effective variable dependent upon several parameters, including, but not limited to:
the nucleotide sequence of the RNAi molecule [parameter 1]; and
the concentration of the RNAi molecule introduced into the host T cell [parameter 2].
The claim is considered to lack adequate written description for failing to recite the structure/function and/or method step(s)/function nexus of the RNAi molecule nucleotide sequence(s) [structure 1] and/or the corresponding working concentration(s), respectively [structure 2/method step] that necessarily and predictably causes at least 70% reduction of EBAG9 expression [function].
Parameter 1
The claims recite the RNA interfering molecules comprises at least 18-40 nucleotides, whereby the specification discloses the RNA interfering molecules may be a long as 50, 40, 30, 25, or 20 nucleotides (e.g. pg 7, line 40; pg 8, line 3).
4^50 = 1x10^30 structurally and functionally undisclosed nucleic acid molecules.
4^40 = 1x10^24 structurally and functionally undisclosed nucleic acid molecules.
4^30 = 1x10^18 structurally and functionally undisclosed nucleic acid molecules.
4^25 = 1x10^15 structurally and functionally undisclosed nucleic acid molecules.
4^20 = 1x10^12 structurally and functionally undisclosed nucleic acid molecules.
(www.calculator.net/exponent-calculator.html; last visited July 15, 2025; of record)
Thus, the claims reasonably encompass an enormously vast genus of about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules directed to an EBAG9 mRNA transcript.
Applicant’s working examples are directed to SEQ ID NO’s: 1-2 and 55-62, each of which consist of 21 nucleotides.
Parameter 2
The claims fail to recite the working concentration(s) of the enormously vast genus of about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules directed to an EBAG9 mRNA transcript with which to necessarily and predictably achieve the functional properties of:
not more than 70% reduced;
not more than 73% reduced;
not more than 76% reduced;
not more than 79% reduced;
etc…
The specification discloses that not all RNA interfering sequences that target EBAG9 yield at least 70% reduction of EBAG9 expression (e.g. pg 55, lines 16-17, “H19 did not effectuate EBAG9 protein downregulation”).
Jackson et al (Widespread siRNA ‘‘off-target’’ transcript silencing mediated by seed region sequence complementarity RNA 12: 1179-1187, 2006; of record) is considered relevant prior art for having taught that base mismatches of the RNA reduced hybridization to the on-target sequence, and instead generated off-target hybridization with sequences complementary to the mismatched sequence (e.g. Abstract). Complementarity to nucleotides centrally within the RNA oligonucleotide can generate off-target hybridization (e.g. pg 1180, col. 1). Furthermore, not all transcripts with at least 7 nucleotides of sequence complementarity to the seed region of an siRNA molecule are actually silenced by siRNAs and shRNAs. Rather, functional targets contain additional specificity determinants (e.g. pg 1185, col. 1).
Naiser et al (Impact of point-mutations on the hybridization affinity of surface-bound DNA/DNA and RNA/DNA oligonucleotide-duplexes: Comparison of single base mismatches and base bulges, BMC Biotechnol. 8(48): 23 pages, doi: 10.1186/14712-6750-8-48, 2008; of record) is considered relevant prior art for having taught nucleic acid hybridization experiments using oligonucleotides varying in length from 16 to 40 nucleotides (e.g. Abstract).
Naiser et al taught that nucleotide mismatches located centrally within the oligonucleotide significantly negatives hybridization to a target sequence (e.g. Figure 1, “defect position”; Figure 2, “mismatch base position”).
Naiser et al taught that in addition to the hybridization defects caused by single nucleotide mismatches or bulges that negative hybridization affinity, there is also a sequence dependence, which extends beyond the defect next-neighbor and which is difficult to quantify (e.g. Abstract).
Zhang et al (Optimizing the specificity of nucleic acid Hybridization, Nature Chemistry 4: 208-214, 2012; of record) is considered relevant prior art for having taught that specific hybridization of complementary sequences is an essential property of nucleic acids; however, the specificity of hybridization is compromised for long strands. The hybridization of long nucleic acids may be non-specific, except near the melting temperatures, whereby those of ordinary skill in the art immediately recognize that such high temperatures do not exist in living cells (e.g. Abstract, Introduction).
Fakler et al (Short Antisense Oligonucleotide-mediated Inhibition Is Strongly Dependent on Oligo Length and Concentration but Almost Independent of Location of the Target Sequence, J. Biol. Chem. 269 (23): 16187-16194, 1994; of record) is considered relevant prior art for having taught that the ability of an antisense oligonucleotide to inhibit its target gene expression is a variable functional property dependent both on the oligonucleotide length [parameter 2] and working concentration [parameter 4] (e.g Title).
Ki et al (The optimal concentration of siRNA for gene silencing in primary cultured astrocytes and microglial cells of rats, Korean J. Anethsiol. 59(6): 403-410, 2010; of record) is considered relevant prior art for having taught that the ability of an siRNA to inhibit its target gene expression is a variable functional property dependent both on the working concentration [parameter 4] and the target host cell (e.g Figure 5; astrocytes vs microglial cells; 5nM vs 10nM, 20nM, 40nM, and/or 80nM; Figure 6).
The claims fail to recite, and the specification fails to disclose, a first RNAi nucleic acid sequence of the enormously vast genus about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules [parameter 1] and it’s respective working concentration(s) [parameter 2] that will necessarily and predictably yield at least a 10% reduction in EBAG9 expression, for example.
The claims fail to recite, and the specification fails to disclose, a first RNAi nucleic acid sequence of the enormously vast genus about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules, and it’s respective working concentration(s), that will necessarily and predictably yield at least a 10% reduction in EBAG9 activity, as opposed to a second RNAi nucleic acid sequence of the enormously vast genus about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules, and it’s respective working concentration(s), that will necessarily and predictably yield:
at least a 20%, but not 30%, 40%, 50%, 60%, 70%, 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 30%, but not 40%, 50%, 60%, 70%, 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 40%, but not 50%, 60%, 70%, 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 50%, but not 60%, 70%, 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 60%, but not 70%, 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 70%, but not 80%, 90%, and/or 100% reduction in EBAG9 expression;
at least a 80%, but not 90%, and/or 100% reduction in EBAG9 expression; and/or
at least a 90%, but not 100% reduction in EBAG9 expression, for example.
Rather, the only RNAi nucleic acid species disclosed are the 10 RNAi SEQ ID NO’s 1-2 and 55-62, each 21 nucleotides in length and 100% complementary to a target sequence of EBAG9 RNA (pg 6, lines 22-33).
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)
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 RNA interference molecule is to be a nucleic acid molecule does not tell you anything at all about the structure (nucleic acid sequences) of the enormously vast genus about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules [parameter 1], and it’s respective working concentration(s) [parameter 2], such that downregulated expression of said target gene will, be it directly or indirectly, necessarily and predictably yield a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and/or 100% reduction in EBAG9 expression, concordantly and respectively, for example.
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 Applicant claims an enormously vast genus about 1x10^30, 1x10^24, 1x10^18, 1x10^15, and/or 1x10^12 structurally undisclosed RNA interfering nucleic acid molecules.
“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 ten RNA interfering molecules whose nucleotide sequences comprise SEQ ID NO:1-2 and 55-62, each 21 nucleotides in length and 100% complementary to a target sequence of EBAG9 RNA (e.g. pg 6, lines 22-33).
Instant specification fails to make up for the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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).
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.
8. Claims 1, 6, 8-11, 13, 15, 18, 20, and 22-23 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ruder et al (2009; Applicant’s own work; of record in IDS) in view of Perna et al (2015; of record), Okamoto et al (2009; of record in IDS) and Sonoda et al (2007; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Ruder et al (Applicant) is considered relevant prior art for having taught a genetically modified cytotoxic T cell (CTL) comprising one or more exogenous nucleic acid molecules encoding a transgenic antigen-targeting construct, wherein in said cells estrogen receptor-binding fragment-associated antigen 9 (EBAG9) activity is inhibited (e.g. pg 2188, col. 2, OT-1 KO T cells).
Ruder et al taught that CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (e.g. Abstract; pgs 2139-2140, Discussion).
Ruder et al taught that, “estrogen induces gene activation of EBAG9. Since estrogen receptor expression on CD4+ and CD8+ T cells has been recorded, EBAG9 would be in a position to modulate the cytolytic T cell responsiveness toward antigenic target cells, depending on the prevalent estrogen levels. In view of the suggested immunosurveillance function of CTLs in cancer, the potential therapeutic benefit of estrogen activity inhibition warrants further study.” (pg 2197, col. 2, Conclusion).
Thus, Ruder et al reasonably infers or implies the use of the genetically modified CTLs comprising inhibited EBAG9 activity in methods of treating cancer.
Ruder et al taught the exogenous nucleic acid encodes an antigen-specific TCR, not a chimeric antigen receptor.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 1 and 8, Perna et al is considered relevant prior art for having taught methods of treating cancer in a subject, wherein the cytotoxic T cell (CTL) immunotherapies for the treatment of cancer, e.g. Non-Hodgkin’s Lymphoma (NHL), may be genetically modified to express an antigen-specific TCR (e.g. pg 59, col. 1) or a chimeric antigen receptor (e.g. pg 60, col. 1).
Ruder et al do not teach the genetically modified cytotoxic T cells were modified using a nucleic acid vector encoding an antigen-targeting construct and an RNA interfering sequence to knock-down EBAG9.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 1, 6, 15, and 18, Okamoto et al is considered relevant prior art for having taught a nucleic acid construct encoding an antigen-targeting construct and an RNA interfering sequence (e.g. pg 9004, col. 1, “We designed the siRNA sequences…”) for the artisan’s target gene of interest (e.g. Figure 1b, c, d), and introducing said nucleic acids into a population of peripheral blood monocytes comprising CD4+ and CD8+ T cells (entire paper; e.g. pg 9006, col. 2, “C-optiTCR-transduced T cells”), wherein said genetically modified CTLs demonstrated enhanced tumor-specific CTL activity in an in vitro assay (e.g. Figure 5, legend, cytotoxicity assays).
Sonoda et al is considered relevant prior art for having taught the use of siRNA molecules to substantially reduce and or essentially eliminate EBAG9 expression (syn. RCAS1; pg 1988, col. 1) (e.g. Figure 1a, siRNA#4, siRNA#20).
Sonoda et al do not teach ipsis verbis the nucleotide sequence of the EBAG9 mRNA expressed in the human cells.
However, said human EBAG9 mRNAs are considered to reasonably fulfill instant recitation of “according to SEQ ID NO:3-6”.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art human EBAG9 mRNA sequence and the claimed invention human EBAG9 mRNA SEQ ID NO’s: 3-6 may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cloning, and the creation of transgenic cells and organisms. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
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 exogenous nucleic acid encoding an antigen-specific TCR, as taught by Ruder et al, with a second exogenous nucleic acid encoding an antigen-specific chimeric antigen receptor, as taught by Perna et al, in a genetically modified cytotoxic T cells (CTLs) in which EBAG9 activity is inhibited 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. An artisan would be motivated to substitute a first exogenous nucleic acid encoding an antigen-specific TCR with a second exogenous nucleic acid encoding an antigen-specific chimeric antigen receptor in a genetically modified cytotoxic T cells in which EBAG9 activity is inhibited because those of ordinary skill in the art previously recognized the scientific and technical concepts, and successfully reduced to practice, that cytotoxic T cell (CTL) immunotherapies for the treatment of cancer may genetically modified to express a heterologous antigen-specific TCR or an antigen-specific chimeric antigen receptor.
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” Those of ordinary skill in the art immediately recognize that there are but two options: a heterologous antigen-specific TCR or a heterologous antigen-specific chimeric antigen receptor.
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 first means of inhibiting EBAG9 activity, as taught by Ruder et al, with a second means of inhibiting EBAG9 activity via siRNA, as taught by Sonoda et al, 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. An artisan would be motivated to substitute a first means of inhibiting EBAG9 activity with a second means of inhibiting EBAG9 activity via siRNA because RNA interference technology, including delivery of siRNA, has long been routinely practiced in the art, as successfully demonstrated by Sonoda et al.
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 modify the method of Ruder et al to genetically modify a CTL population to comprise a heterologous antigen-targeting construct and an RNA interfering sequence for knock-down of EBAG9 with a reasonable expectation of success because those of ordinary skill in the art immediately recognize that the Ruder et al model required transgenic mice to generate the genetically modified CTL population, which simply is not practical for the generation of antigen-specific genetically modified CTL populations for effective immunotherapy in cancer patients (e.g. Okamoto et al, Abstract). Rather, a single vector encoding the artisan’s heterologous antigen-targeting construct and an RNA interfering sequence for knock-down of EBAG9 is but routine molecular biology, as successfully demonstrated by Okamoto et al and Sonoda et al, for which the ordinary artisan has long-recognized that siRNA molecules directed against EBAG9 will successfully and predictably reduce EBAG9 expression levels, thereby inhibiting EBAG9 activity in the thus-transduced CTL cells.
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).
With respect to Claim 15, while it is clear that the claim encompasses the genetically modified CTLs be cultured in vitro, the claim does not require the cytotoxic T cells to be genetically modified in vitro. Ruder et al generated the genetically modified T cells in vivo by crossing two different mouse strains together (e.g. pg 2188, col. 1, “we backcrossed…”). Ruder et al taught the step of culturing the genetically modified CTLs be cultured in vitro (e.g. Figure 4, legend, “by in vitro culture”; Figure 5, legend, “priming…in vitro”).
Those of ordinary skill in the art immediately recognize that the CAR T cells (e.g. Perna et al) are routinely manufactured in vitro prior to administration in vivo (e.g. Perna et al, pg 58, col’s 1-2, joining para, “manufacturing procedures”; pg 63, citation 41, “manufactured at clinical scale”).
With respect to Claim 13, Ruder et al (Applicant) taught a pharmaceutical composition comprising the genetically modified cytotoxic T cells (e.g. pg 2188, col. 2, “adoptively transferred…into congenic hosts”).
Perna et al evidence that those of ordinary skill in the art had long-recognized and successfully reduced to practice formulating the cytotoxic T cells genetically modified to express an antigen-specific TCR or a chimeric antigen receptor into a pharmaceutical composition for the treatment of cancer (e.g. Table 1, clinical trials). Those of ordinary skill in the art immediately recognize that the CAR T cells (e.g. Perna et al) are routinely manufactured in vitro prior to administration in vivo (e.g. Perna et al, pg 58, col’s 1-2, joining para, “manufacturing procedures”; pg 63, citation 41, “manufactured at clinical scale”).
Okamoto et al taught the genetically modified CTLs have enhanced tumor-specific cytotoxicity activity (e.g. Figure 5, legend), and thus are suitable for the treatment of a proliferative disease.
With respect to Claims 9-10 and 20, Perna et al taught wherein the antigen targeted by the antigen-targeting construct is expressed in a target hematological malignancy, wherein the hematological malignancy is non-Hodgkin’s lymphoma (e.g. pg 58, col. 2, “Tumor-associated antigen-specific T-cells for the treatment of NHL”; Tables 1-2).
With respect to Claim 11, Perna et al taught wherein the antigen targeted by the antigen-targeting construct is CD19 (e.g. Tables 1-2).
With respect to Claim(s) 6, 15, and 18, Okamoto et al taught a nucleic acid construct encoding an antigen-targeting construct and an RNA interfering sequence (e.g. pg 9004, col. 1, “We designed the siRNA sequences…”) for the artisan’s target gene of interest (e.g. Figure 1b, c, d).
With respect to Claims 22-23, Sonoda et al taught an EBAG9 siRNA (siRNA #4) comprising nucleotide sequences also present in instant SEQ ID NO:2, as shown below:
GAAUGUGGTT
||| :|| |
GAAACTGGGT
Sonoda et al taught an EBAG9 siRNA (siRNA #4) comprising nucleotide sequences also present in instant SEQ ID NO:56, as shown below:
GGAAUGGGAAUGUGGTT
||||:| |||: |||
GGAATGAGAATACTGTT
and thus is considered to reasonably fulfill instant recitation “according to”.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art siRNAs directed against a human EBAG9 mRNA sequence and the claimed invention RNA interference molecules SEQ ID NO’s: 1-2 and 55-62 directed against human EBAG9 mRNA SEQ ID NO’s: 3-6 may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
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 Amendment
The Examiner acknowledges and has considered the Rehm Declaration filed under 37 CFR §1.132 on March 6, 2026.
Rehm declares (para 6-7) that the Examiner’s citation of Ruder et al’s teaching (pg 2197, col. 2, Conclusion) is taken out of context, as it refers to further study on the potential therapeutic benefit of estrogen activity inhibition, not inhibition of EBAG9 activity in methods of treating cancer.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant themselves taught that “estrogen induces activation of EBAG9” (pg 2197, col. 2, Conclusion), and thus the ordinary artisan would have reasonably understood that reference to the therapeutic potential of inhibiting estrogen activity in CTLs in cancer refers to decreasing or reducing EBAG9 activity (via estrogen inhibition, no EBAG9 induction) in said CTLs in cancer.
Thus, Ruder et al reasonably infers or implies CTLs comprising inhibited EBAG9 activity in methods of treating cancer, for which the ordinary artisan would reasonably and logically infer using Ruder et al’s exemplary CTLs genetically modified to reduce or inhibit EBAG9 expression.
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).
Rehm declares (para 9 and 12-15) that the in vivo experiments of Ruder et al were not carried out in a cancer setting, but rather an infection model.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Ruder et al taught that CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (e.g. Abstract; pgs 2139-2140, Discussion).
Ruder et al reasonably infers or implies the use of the genetically modified CTLs comprising inhibited EBAG9 activity in methods of treating cancer (see discussion above).
Perna et al is considered relevant prior art for having taught methods of treating cancer in a subject, wherein the cytotoxic T cell (CTL) immunotherapies for the treatment of cancer, e.g. Non-Hodgkin’s Lymphoma (NHL), may be genetically modified to express an antigen-specific TCR (e.g. pg 59, col. 1) or a chimeric antigen receptor (e.g. pg 60, col. 1).
Okamoto et al is considered relevant prior art for having taught a nucleic acid construct encoding an antigen-targeting construct and an RNA interfering sequence (e.g. pg 9004, col. 1, “We designed the siRNA sequences…”) for the artisan’s target gene of interest (e.g. Figure 1b, c, d), and introducing said nucleic acids into a population of peripheral blood monocytes comprising CD4+ and CD8+ T cells (entire paper; e.g. pg 9006, col. 2, “C-optiTCR-transduced T cells”), wherein said genetically modified CTLs demonstrated enhanced tumor-specific CTL activity in an in vitro assay (e.g. Figure 5, legend, cytotoxicity assays).
Sonoda et al is considered relevant prior art for having taught the use of siRNA molecules to substantially reduce and or essentially eliminate EBAG9 expression (syn. RCAS1; pg 1988, col. 1) (e.g. Figure 1a, siRNA#4, siRNA#20).
Rehm declares (para 10-11) that although Ruder et al demonstrated enhanced granzyme A secretion from EBAG9-deficient CTLs, and that EBAG9 inhibition led to enhanced primary immune responses in vivo against a target antigen, the experiments were not in a cancer setting, and it remained uncertain as to whether EBAG9 inhibition in a CAR T cell directed against a tumor antigen would also lead to enhanced T cell activity.
Applicant’s argument(s) has been fully considered, but is not persuasive.
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 exogenous nucleic acid encoding an antigen-specific TCR, as taught by Ruder et al, with a second exogenous nucleic acid encoding an antigen-specific chimeric antigen receptor, as taught by Perna et al, in a genetically modified cytotoxic T cells (CTLs) in which EBAG9 activity is inhibited 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. An artisan would be motivated to substitute a first exogenous nucleic acid encoding an antigen-specific TCR with a second exogenous nucleic acid encoding an antigen-specific chimeric antigen receptor in a genetically modified cytotoxic T cells in which EBAG9 activity is inhibited because those of ordinary skill in the art previously recognized the scientific and technical concepts, and successfully reduced to practice, that cytotoxic T cell (CTL) immunotherapies for the treatment of cancer may genetically modified to express a heterologous antigen-specific TCR or an antigen-specific chimeric antigen receptor.
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” Those of ordinary skill in the art immediately recognize that there are but two options: a heterologous antigen-specific TCR or a heterologous antigen-specific chimeric antigen receptor.
Ruder et al taught that CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (e.g. Abstract; pgs 2139-2140, Discussion).
Ruder et al taught that, “estrogen induces gene activation of EBAG9. Since estrogen receptor expression on CD4+ and CD8+ T cells has been recorded, EBAG9 would be in a position to modulate the cytolytic T cell responsiveness toward antigenic target cells, depending on the prevalent estrogen levels. In view of the suggested immunosurveillance function of CTLs in cancer, the potential therapeutic benefit of estrogen activity inhibition warrants further study.” (pg 2197, col. 2, Conclusion).
Thus, Ruder et al reasonably infers or implies the use of the genetically modified CTLs comprising inhibited EBAG9 activity in methods of treating cancer.
As discussed in the prior Office Action, the Examiner provides the following reference to rebut applicant’s arguments regarding the state of the prior art regarding the ability of EBAG9 knockout cytotoxic T cells to be efficacious in the treatment of cancer in a subject. Note: the reference is not considered a part of the 103 rejection but is solely provided to rebut applicant’s argument(s).
Miyazaki et al (EBAG9 modulates host immune defense against tumor formation and metastasis by regulating cytotoxic activity of T lymphocytes, Oncogenesis 3: e126, 8 pages, doi:10.1038/oncsis.2014.40; available online November 3, 2014; of record in IDS) is considered relevant prior art for having taught a method of treating cancer in a wildtype mouse subject, the method comprising the step of administering to said subject a pharmaceutical composition comprising cytotoxic tumor-infiltrating EBAG9 knockout CD8+ T cells that recognize an antigen expressed on the cancer cells, whereby tumor infiltration of CD8+, CD3+, and CD4+ EBAG9 knockout T cells was enhanced, as compared to wildtype controls, and that CD8+ T cells isolated from tumors in EBAG9 knockout mice exhibited substantial upregulation of immunity- and chemoattraction-related genes, including interleukin-10 receptor, interferon gamma, granzyme A, granzyme B and chemokine (C-X-C motif) receptor 3, and exhibited enhanced degranulation and increased cytolytic activity, as compared with CD8+ T cells from tumors in control mice.
Obviousness does not require absolute predictability, however, at least some degree of predictability is required. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) See MPEP §2143.02.
At least 5 years before the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized that the adoptive transfer of EBAG9 knockout CD8+ T cells could significantly repress tumor growth by MB-49 cells implanted in wild-type host. (e.g. Abstract; pg 3, col. 2, “significantly inhibited tumor growth…., compared with those from control mice”; Figure 3c).
Rehm declares (para 17) that the beneficial properties of the claimed CAR T cells, e.g. without an increase in off-target effects, enhanced cytolytic function against cancer antigens-expressing target cells with a low target antigen density, are not a predictable result.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., without an increase in off-target effects, enhanced cytolytic function against cancer antigens-expressing target cells with a low target antigen density) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
All that is required by the instantly claimed CAR T cells is that they comprise RNA interfering molecules directed to human EBAG9 mRNA transcripts, and that EBAG9 expression is, at least temporarily, reduced by 70%, retaining as much as 30% residual EBAG9 expression and activity.
However, the cited prior art taught EBAG9 knockout (syn. 100% reduction of EBAG9 expression) or the use of siRNAs directed to human EBAG9 mRNA transcripts, and that EBAG9 expression is reduced to nearly 100% (Sonoda et al, Figure 1a, e.g. siRNA #20).
In response to applicant's argument that the claimed CAR T cells have beneficial properties such as without an increase in off-target effects, enhanced cytolytic function against cancer antigens-expressing target cells with a low target antigen density, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Ruder et al taught that CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (e.g. Abstract; pgs 2139-2140, Discussion).
Rehm declares (para 18) that post-filing work (Wirges et al, 2022, Exhibit A) demonstrated enhanced cytolytic activity of EBAG9-inhibited CAR T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. Wirges et al taught that the CAR-T cells were genetically modified with a retroviral vector expressing the miRNAs (e.g. pg 3359, col. 1, “retroviral platform”). See also instant specification (e.g. pg 54, Summary of the Examples, “retroviral expression vector”). Instant independent claims fail to recite this structural limitation.
Those of ordinary skill in the art would immediately recognize that transient expression of RNA interfering molecules do not yield the same functional properties as constitutive and long-term expression of RNA interfering molecules (Wirges et al, up to Day 19/20 (e.g. Figure 1d) because EBAG9 expression will be restored after degradation of the transient RNA interfering molecules per natural law of cell biology, a condition not present in the CAR-T cells genetically modified with the retroviral expression vector constitutively expressing the RNA interfering molecule(s).
See, for example, Lamberton et al (Varying the Nucleic Acid Composition of siRNA Molecules Dramatically Varies the Duration and Degree of Gene Silencing, Molecular Biotechnology 24: 111-119, 2003) who taught transient transfection of RNA interfering molecules into mammalian host cells, including human cells, whereby the siRNAs achieved about 60% target gene silencing in the first 24 hours, but began to regain target gene expression at 48 hours post-transfection, and exhibited full target gene expression by 96 hours (syn. 4 days) post-transfection (e.g. pg 114, col. 2).
Thus, instant claims are not commensurate in scope with asserted secondary considerations.
Instant independent claims fail to recite that the CAR-T cells genetically modified with the retroviral expression vector constitutively expressing the RNA interfering molecule(s).
Rehm declares (para 20-24) that Wirges et al (2022) teach administration of 5x10^6 EBAG9-RNAi-modified BCMA CAR T cells to a mouse xenograft model.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Instant independent Claim 8, method of treating, nor dependent Claims 9-11 and 20, fail to recite the dosage of the EBAG9-RNAi-modified CAR T cells that are to be administered to the subject. Rather, the claims are recited at a high level of generality. Instant specification discloses an example of administering 1x10^6 CAR T cells to a mouse tumor xenograft subject (e.g. pg 57, line 18).
Thus, instant claims are not commensurate in scope with asserted secondary considerations.
Rehm declares (para 26-29) that enhanced cytolytic efficacy without inducing CAR T cell cellular exhaustion is a property that is of importance in and unique to a CAR T cell context.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., without an increase in off-target effects, enhanced cytolytic function against cancer antigens-expressing target cells with a low target antigen density) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
All that is required by the instantly claimed CAR T cells is that they comprise RNA interfering molecules directed to human EBAG9 mRNA transcripts, and that EBAG9 expression is reduced by 70%, retaining as much as 30% residual EBAG9 expression.
However, the cited prior art taught EBAG9 knockout (syn. 100% reduction of EBAG9 expression) or the use of siRNAs directed to human EBAG9 mRNA transcripts, and that EBAG9 expression is reduced to nearly 100% (Sonoda et al, Figure 1a, e.g. siRNA #20).
In response to applicant's argument that the claimed CAR T cells have beneficial properties such as without an increase in off-target effects, enhanced cytolytic function against cancer antigens-expressing target cells with a low target antigen density, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Ruder et al taught that CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (e.g. Abstract; pgs 2139-2140, Discussion).
9. Claims 8-10 and 13 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ruder et al (2009; Applicant’s own work; of record in IDS) in view of Perna et al (2015; of record), Okamoto et al (2009; of record in IDS) and Sonoda et al (2007; of record in IDS), as applied to Claims 1, 6, 8-11, 13, 15, 18, 20, and 22-23 above, and in further view of Miyazaki et al (available online November 3, 2014; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Miyazaki et al is considered relevant prior art for having taught a method of treating cancer in a mouse subject, the method comprising the step of administering to said subject a pharmaceutical composition comprising cytotoxic tumor-infiltrating EBAG9 knockout CD8+ T cells that recognize an antigen expressed on the cancer cells.
Miyazaki et al taught that tumor infiltration of CD8+, CD3+, and CD4+ EBAG9 knockout T cells was enhanced, as compared to wildtype controls, and that CD8+ T cells isolated from tumors in EBAG9 knockout mice exhibited substantial upregulation of immunity- and chemoattraction-related genes, including interleukin-10 receptor, interferon gamma, granzyme A, granzyme B and chemokine (C-X-C motif) receptor 3, and exhibited enhanced degranulation and increased cytolytic activity, as compared with CD8+ T cells from tumors in control mice. The adoptive transfer of EBAG9 knockout CD8+ T cells could significantly repress tumor growth by MB-49 cells implanted in wild-type host. (e.g. Abstract; pg 3, col. 2, “significantly inhibited tumor growth…., compared with those from control mice”; Figure 3c).
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 also would have been obvious to one of ordinary skill in the art to arrive at a method of treating cancer in a subject comprising the step of administering to said subject a genetically modified cytotoxic T cell that recognizes a tumor antigen and in which endogenous EBAG9 expression is knocked-out with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) CTLs are known in the art to eliminate tumorigenic cells, whereby the inhibition of EBAG9 activity in the CTLs results in an increase in CTL cytotoxicity against antigen-specific target cells and enhanced cytolytic primary and memory T cell responses in vivo, killing their targets more efficiently than CTLs in which EBAG9 activity was not inhibited (Ruder et al, Abstract; pgs 2139-2140, Discussion), whereby EBAG9 would be in a position to modulate the cytolytic T cell responsiveness toward antigenic target cells, depending on the prevalent estrogen levels. In view of the suggested immunosurveillance function of CTLs in cancer, the potential therapeutic benefit of estrogen activity inhibition warrants further study.” (pg 2197, col. 2, Conclusion), and thus reasonably infers or implies the use of the genetically modified CTLs comprising inhibited EBAG9 activity in methods of treating cancer;
ii) methods of treating cancer in a subject, wherein the cytotoxic T cell (CTL) immunotherapies for the treatment of cancer, e.g. Non-Hodgkin’s Lymphoma (NHL), may be genetically modified to express an antigen-specific TCR (Perna et al, e.g. pg 59, col. 1) or a chimeric antigen receptor (e.g. pg 60, col. 1); and
iii) Miyazaki et al successfully demonstrated the ability to administer to a cancer subject a pharmaceutical composition comprising cytotoxic EBAG9 knockout CD8+ T cells that recognize an antigen expressed on the cancer cells, whereby the tumor infiltration of CD8+, CD3+, and CD4+ EBAG9 knockout T cells was enhanced, as compared to wildtype controls, that CD8+ T cells isolated from tumors in EBAG9 knockout mice exhibited substantial upregulation of immunity- and chemoattraction-related genes, including interleukin-10 receptor, interferon gamma, granzyme A, granzyme B and chemokine (C-X-C motif) receptor 3, and exhibited enhanced degranulation and increased cytolytic activity, as compared with CD8+ T cells from tumors in control mice, and the adoptive transfer of EBAG9 knockout CD8+ T cells could significantly repress tumor growth by MB-49 cells implanted in wild-type host. (e.g. Abstract; pg 3, col. 2, “significantly inhibited tumor growth…., compared with those from control mice”; Figure 3c).
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).
With respect to Claim 13, Ruder et al (Applicant) taught a pharmaceutical composition comprising the genetically modified cytotoxic T cells (e.g. pg 2188, col. 2, “adoptively transferred…into congenic hosts”).
Perna et al evidence that those of ordinary skill in the art had long-recognized and successfully reduced to practice formulating the cytotoxic T cells genetically modified to express an antigen-specific TCR or a chimeric antigen receptor into a pharmaceutical composition for the treatment of cancer (e.g. Table 1, clinical trials). Those of ordinary skill in the art immediately recognize that the CAR T cells (e.g. Perna et al) are routinely manufactured in vitro prior to administration in vivo (e.g. Perna et al, pg 58, col’s 1-2, joining para, “manufacturing procedures”; pg 63, citation 41, “manufactured at clinical scale”).
Okamoto et al taught the genetically modified CTLs have enhanced tumor-specific cytotoxicity activity (e.g. Figure 5, legend), and thus are suitable for the treatment of a proliferative disease.
Miyazaki et al taught a pharmaceutical composition comprising cytotoxic EBAG9 knockout CD8+ T cells that recognize an antigen expressed on the cancer cells (e.g. pg 7, col. 1, Methods, Adaptive CD8+ T-cell transfer).
With respect to Claims 9-10, Perna et al taught wherein the antigen targeted by the antigen-targeting construct is expressed in a target hematological malignancy, wherein the hematological malignancy is non-Hodgkin’s lymphoma (e.g. pg 58, col. 2, “Tumor-associated antigen-specific T-cells for the treatment of NHL”; Tables 1-2).
Miyazaki et al taught the cytotoxic EBAG9 knockout CD8+ T cells were isolated from tumors, syn. tumor-infiltrating lymphocytes, for which those of ordinary skill in the art immediately recognize that said cytotoxic TILs naturally recognize an antigen expressed on the cancer cells.
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.
10. Claims 8-11 and 20 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ruder et al (2009; Applicant’s own work; of record in IDS) in view of Perna et al (2015; of record), Okamoto et al (2009; of record in IDS), and Sonoda et al (2007; of record in IDS), as applied to Claims 1, 6, 8-11, 13, 15, 18, 20, and 22-23 above, and in further view of Algate et al (U.S. 2018/0147293; published May 31, 2018; priority to at least May 24, 2012; of record) and DiPersio et al (U.S. 2020/0040056; priority to 62/678,883 filed May 31, 2018; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Perna et al taught wherein the antigen targeted by the antigen-targeting construct is CD19 (e.g. Tables 1-2) or MAGE-A4, a tumor antigen for non-Hodgkin’s lymphoma (e.g. pg 58, col. 2, “Tumor-associated antigen-specific T-cells for the treatment of NHL”; pg 59, col. 1, “NHLs frequently express…MAGE-A4”).
Okamoto et al taught the antigen-specific receptor is specific for MAGE-A4 (e.g. pg 9003, col. 2; Figure 1).
Neither Perna et al nor Okamoto et al teach wherein the antigen-targeting construct targets the tumor antigen BCMA.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 8-11 and 20, Algate et al is considered relevant prior art for having disclosed an antigen-targeting construct that recognizes BCMA (e.g. claim 1), wherein said antigen-targeting construct is used in a method of treating cancer in a patient, to wit, non-Hodgkin’s lymphoma (e.g. claim 17).
Similarly, DiPersio et al is considered relevant prior art for having disclosed genetically modified immune cells expressing a heterologous antigen-targeting construct that recognizes BCMA (e.g. claim 7; as also disclosed in 62/678,883, claim 7), wherein said genetically modified immune cells are used in a method of treating cancer in a patient, to wit, non-Hodgkin’s lymphoma (e.g. claim 63; as also disclosed in 62/678,883, claim 22).
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 target antigen expressed on NHL cancer cells, as taught by Okamoto et al, with a second target antigen expressed on NHL cancer cells, to wit, BCMA, as disclosed by Algate et al and DiPersio et al, in a method of treating a hematological malignancy, more specifically, non-Hodgkin’s lymphoma, with a genetically modified CTL population comprising a heterologous antigen-targeting construct and an RNA interfering sequence for knock-down of EBAG9 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. An artisan would be motivated to substitute a first target antigen expressed on NHL cancer cells with a second target antigen expressed on NHL cancer cells, to wit, BCMA, in a method of treating a hematological malignancy, more specifically, non-Hodgkin’s lymphoma, with a genetically modified CTL population comprising a heterologous antigen-targeting construct and an RNA interfering sequence for knock-down of EBAG9 because BCMA was a previously known target antigen for NHL for methods of treating patients suffering from NHL, including the use of genetically modified immune cells expressing an antigen-targeting construct that specifically binds BCMA.
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).
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.
11. Claims 22-23 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ruder et al (2009; Applicant’s own work; of record in IDS) in view of Perna et al (2015; of record), Okamoto et al (2009; of record in IDS), and Sonoda et al (2007; of record in IDS), as applied to Claims 1, 6, 8-11, 13, 15, 18, 20, and 22-23 above, and in further view of Aalto et al (Large-scale production of dsRNA and siRNA pools for RNA interference utilizing bacteriophage f6 RNA-dependent RNA polymerase, RNA 13: 422-429, 2007) and Hannus et al (siPools: highly complex but accurately defined siRNA pools eliminate off-target effects, Nucleic Acids Res. 42(12): 8049-8061, 2014).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Sonoda et al do not teach wherein the siRNA comprises a nucleotide sequence identical to instant SEQ ID NO’s: 1-2 or 55-62.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 22-23, Aalto et al is considered relevant prior art for having taught the synthesis of a pooled combination of siRNAs directed to the same target mRNA (e.g. Abstract, "pools of siRNAs decreased the expression of a transgene"; pg 423, col. 1, "siRNA pools for entire genes". Aalto et al taught that the dsRNA was enzymatically digested with recombinant Dicer, thereby creating the siRNA pools (e.g. pg 424, col. 2). Aalto et al taught that because several factors affect the efficacy of an siRNA, identifying a functional sequence is often laborious and expensive, whereby the problem can be circumvented by using siRNA pools containing molecules of different sequences (e.g. pg 422, col. 2). Aalto et al taught that because each siRNA has its own off-targets, pooling is thought to reduce the individual nonspecific contributions of each sequence, revealing the "true" RNAi phenotype (e.g. pg 426, col. 2).
Similarly, Hannus et al is considered relevant prior art for having taught one of the major shortcomings of siRNA are sequence-specific off-target effects, which are largely unpredictable. However, the use of a pooled combination of siRNAs (syn. siRNA pool) can eliminate off -target effects because each individual siRNA is present in the pool at low concentrations, diluting sequence-specific off-target effects below detection limits. While single siRNA transfections can severely affect global gene expression, there is almost no transcriptome alteration when using complex siRNA pools (Abstract). Hannus et al taught the RNA template was enzymatically digested with RNAse to create the siRNA pools (e.g. pg 8050, col. 1, Methods). Hannus et al taught the pooled combination of siRNAs target a single gene (e.g. pg 8050, col. 1, "synergistically silencing one single on-target gene").
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 modify a method of reducing or silencing EBAG9 expression via the introduction of RNA interference molecules directed against a target sequence within a human EBAG9 mRNA transcript, as taught by Sonoda et al, with siRNA pools, as taught by Aalto et al and Hannus et al, comprising RNA interfering molecules whose nucleotide sequences are identical to and/or substantially overlap with instant SEQ ID NO’s: 1-2 or 55-62, respectively, directed against multiple targets within a human EBAG9 mRNA transcript with a reasonable expectation of success and motivation because:
i) those of ordinary skill in the art previously recognized and successfully reduced to practice siRNA molecules complementary to a human EBAG9 mRNA, thereby silencing EBAG9 expression in a host cell (Sonoda et al);
ii) those of ordinary skill in the art would have immediately recognized that, per natural law of chemistry and enzymology, the siRNA pools directed against EBAG9 mRNA, generated per Aalto et al and/or Hannus et al, would comprise RNA interfering molecules identical to and/or substantially overlap with instant SEQ ID NO’s: 1-2 or 55-62, respectively; and
iii) those of ordinary skill in the art previously recognized and successfully reduced to practice a pooled combination of siRNA molecules complementary to the same target gene mRNA (Aalto et al, Hannus et al), thereby overcoming and reducing the problem of off-target effects of the individual nonspecific contributions of each siRNA sequence, as each individual siRNA is present in the pool at low concentrations, diluting sequence-specific off-target effects below detection limits, such that there is almost no transcriptome alteration when using complex siRNA pools, and successfully achieving "synergistically silencing one single on-target gene".
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art siRNAs directed against a human EBAG9 mRNA sequence and the claimed invention RNA interference molecules SEQ ID NO’s: 1-2 and 55-62 directed against human EBAG9 mRNA SEQ ID NO’s: 3-6 may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Instant specification fails to disclose an element of criticality for the RNA interference molecules consisting of SEQ ID NO’s: 1-2 and 55-62, as opposed to siRNA #4 and siRNA #20 of Sonoda et al, and/or as opposed to siRNA pools directed against human EBAG9 mRNA transcripts per the methods of Aalto et al and/or Hannus et al.
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).
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.
Citation of Relevant Prior Art
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kunkele et al (Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD, Cancer Immunol. Res. 3(4): 368-379, 2015; of record) is considered relevant prior art for having successfully demonstrated the ability to express an immunomodulatory siRNA in CAR T cells (e.g. pg 372, col. 2, “we subjected [CAR T cells] to siRNA knockdown”), thereby reducing the CAR T cell susceptibility to activation-induced cell death, which would improve clinical activity against the target cancers (e.g. pg 372, col. 2, “observed…increase in T cell viability” after three rounds of exposure to target tumor cells).
Conclusion
13. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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