Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 31, 2026 has been entered.
Detailed Action
This action is in response to the papers filed March 31, 2026.
Amendments
Applicant's response and amendments, filed March 31, 2026, to the prior Office Action is acknowledged.
Applicant has cancelled Claims 1-89 and 91, amended Claims 90, added new claims, Claims 95-116, and withdrawn Claims 100-105.
Claims 90 and 92-116 are pending.
Election/Restrictions
Applicant has elected with traverse the species:
i) the alternative distinctly different structural modifications of the RNA(s) is modified to comprise the specific amino acid SEQ ID NO:4 (p53) and SEQ ID NO:8 (PRAME), as recited in Claim 3; and
ii) the alternative additional therapeutic method step is an anti-cancer agent, as recited in Claim 81.
Claims 90 and 92-116 are pending.
Claims 100-105, 98, and 110 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Newly submitted Claims 98 and 110 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claim are directed to nucleic acids encoding non-elected amino acid SEQ ID NO species.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 98 and 110 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 90, 92-97, 99, 106-109, and 111-116 are under consideration.
Priority
This application is a 371 of PCT/EP2020/064180 filed on May 20, 2020.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A copy of foreign patent application EPO PCT/EP2019/062967 filed on May 20, 2020 is filed with the instant application.
The Examiner notes that a copy of PCT/EP2020/064180 filed on May 20, 2020 has not been provided with the instant application.
Information Disclosure Statement
Applicant has filed Information Disclosure Statement on February 3, 2026 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
The Examiner cites below Applicant's own prior art, not cited in an IDS, to wit:
Wagner (Molecular and functional characterization of the candidate tumor antigens placenta specific 1 and claudin 6, Dissertation, Doctor der Naturwissenshaften, Am Fachbereich Biologie der Johannes Gutenberg Universitat Mainz, doi.org/10.25358/openscience-2827, 2014).
Applicant is reminded of their duty to disclose information material to patentability. See MPEP §2001 and 37 C.F.R. 1.56.
The individuals covered by 37 CFR 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question. As set forth by the court in Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972):
[W]e think that it is unfair to the busy examiner, no matter how diligent and well informed he may be, to assume that he retains details of every pending file in his mind when he is reviewing a particular application . . . [T]he applicant has the burden of presenting the examiner with a complete and accurate record to support the allowance of letters patent.
See MPEP §2001.06(b).
Pursuant to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.), a copy of the Applicant's own publication(s) are not provided with the instant Office Action because it is presumed that Applicant has a copy of their own publications, as such is routine practice in the art, and that Applicant has provided their representative with a copy of said publications to establish a prosecution record. However, if Applicant’s representative insists upon receiving a copy of the entire references, then the Examiner will make attempts to provide it in the next Office Action.
Response to Arguments
Applicant argues that citation of Lai-Nag in the IDS filed October 21, 2025 should have been considered because the first page of Lai-Nag provides the full citation.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant should amend the IDS to provide the full citation of Lai-Nag, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known (see MPEP 707.05(e) for electronic documents), as Applicant has done in the Remarks Made in Amendment filed March 31, 2026 (pg 8, lines 2-3).
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
1. Claim 97 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 97 recites the limitations “under (i), (ii), or (iii)” in reference to Claim 92. There is insufficient antecedent basis for this limitation in the claim because Claim 92 fails to recite (i), (ii), and/or (iii).
Appropriate correction is required.
2. Claims 97 and 99 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 90 and 92 recite at least one RNA molecule encoding a CLDN6 polypeptide, a p53 polypeptide, and a PRAME polypeptide.
Claim 99, dependent upon Claim 90, and Claim 97, dependent upon Claim 92, recite wherein each of the CLDN6, p53, and PRAME polypeptides are encoded by a separate RNA.
Such fails to further limit the independent claim(s) because the independent claim(s) requires all three polypeptides to be encoded by the same RNA molecule, not a population of three structurally distinct RNA molecules.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
3. Claim 96 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 92 recites a method comprising the step of intravenous administration of an RNA pharmaceutical composition.
Claim 96, dependent upon Claim 92, recites wherein the RNA pharmaceutical composition is administered intravenously.
Such fails to further limit the independent claim(s) because the independent claim already requires intravenous administration.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
4. Claim 107 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 107 recites the limitation “or is to be formulated as lipoplex particles”.
The phrase “to be formulated as lipoplex particles” is an intended use limitation, which does not contain any further structural limitations with respect to claimed RNA pharmaceutical composition of Claim 90 (see MPEP §2114).
The claim fails to recite, and the specification fails to disclose, a RNA pharmaceutical composition that is “to be formulated as lipoplex particles”, as opposed to a RNA pharmaceutical composition that is not “to be formulated as lipoplex particles”.
Thus, that which is/is not a RNA pharmaceutical composition “to be formulated as lipoplex particles” is considered to be an arbitrary and subjective determination.
Appropriate correction is required.
The Examiner suggests cancellation of “to be formulated”. See, for example, Claim 93, “is formulated as lipoplex particles”.
5. Claims 111-112 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 111-112 recite methods of treating ovarian cancer in a human subject, the method comprising the step of administering to the subject a composition comprising at least one RNA encoding a CLDN6 polypeptide, a p53 polypeptide, and a PRAME polypeptide.
The claim denotes that not all pharmaceutical compositions comprising the at least one RNA encoding:
i) a CLDN6 polypeptide at least 95% identical to SEQ ID NO:1;
ii) a p53 polypeptide at least 95% identical to SEQ ID NO:4; and
iii) a PRAME polypeptide at least 95% identical to SEQ ID NO:8; and/or
not all dosages of said RNA pharmaceuticals (Claim 111, dependent upon Claim 90); and/or
not all pharmaceutical compositions comprising the at least one RNA encoding:
i) a CLDN6 polypeptide identical to SEQ ID NO:1;
ii) a p53 polypeptide identical to SEQ ID NO:4; and
iii) a PRAME polypeptide identical to SEQ ID NO:8; and/or
not all dosages of said RNA pharmaceuticals (Claim 112, dependent upon Claim 108);
will necessarily yield the functional property of “treating ovarian cancer”.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the RNAs expressing the CLDN6, p53, and PRAME polypeptides must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the structure(s) of CLDN6, p53, and PRAME polypeptides [parameter 4]; and
the phenotypic response to be achieved [parameter 5].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are directed to the treatment of humans.
Parameter 2
The claims are directed to intravenous administration of the RNA pharmaceutical composition.
Parameter 3
The claimed methods are recited at a high level of generality for the RNA dosage that is to be administered. The specification discloses (pg 70) that the “effective amount” will depend on the dose; however, the claims fail to recite, and the specification fails to disclose, the RNA dosage.
Parameter 4
The claimed methods are broad for reciting an enormous genus of structurally and functionally undisclosed:
CLDN6 polypeptide variants;
P53 polypeptide variants; and
PRAME polypeptide variants.
The RNA composition of Claim 90, per Claim 111, is broad for encompassing 95% identity to the amino acid sequences of SEQ ID NO’s: 1, 4, and 8, respectively.
CLDN6 SEQ ID NO:1 is 220 amino acids, and thus 95% allows for 11 insertions, deletions, and/or substitutions, yielding a genus of about 2x10^12 structurally undisclosed variants.
P53 SEQ ID NO:4 is 393 amino acids, and thus 95% allows for 20 insertions, deletions, and/or substitutions, yielding a genus of about 1x10^26 structurally undisclosed variants.
PRAME SEQ ID NO:8 is 509 amino acids, and thus 95% allows for 25 insertions, deletions, and/or substitutions, yielding a genus of about 3x10^32 structurally undisclosed variants.
(www.calculator.net/exponent-calculator.html; last visited April 21, 2026)
Fritsch et al (U.S. 2018/0153975) is considered relevant prior art for having disclosed that tumor antigen epitopes may be as many as 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length (e.g. [0018, 30, 54]).
Those of ordinary skill in the art would immediately recognize that the presence of one or more amino acid deletions, insertions, and/or substitutions encompassed by the instant claims will generate an immune response (syn. antibody formation) directed to one or more epitopes not present in the human subject, thereby negativing the corresponding therapeutic response to the RNA composition.
For example, CLDN6 epitope TCVEEKDSKARLVLT present in SEQ ID NO:1 comprising one or more mutations:
TCV*EKDSKARLVLT
TCV*EKDSKAR*VLT
TCVE*DSKARLV*T
T*VEKDS*ARL*LT
For example, P53 epitope AIYKQSQHMTEV present in SEQ ID NO:4 comprising one or more mutations:
AIY*QSQHMTEV
AIYK*SQH*TEV
AI*KQSQHMT*V
AIY*Q*Q*MTEV
For example, PRAME epitope GVLMKGQHLHLET present in SEQ ID NO:8 comprising one or more mutations:
GVL*KGQHLHLET
G*LMKG*HLHLET
GVLM*GQHL*LET
GV*MKG*HL*LET
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claims also denote that there is an amount (syn. dosage) of the RNAs that upon administration to the subject is ineffective or unable to achieve a therapeutic effect.
An (therapeutically) effective amount to do what?
While it is clear the method is to stimulate an immune response, there is a gap in the nexus of “stimulates an immune response” and “treating”.
As discussed below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection, recent attempts on extensive trials of cancer vaccines, using viral structures or substructures against several cancers such as cervices, prostate, lung, pancreatic and skin also failed to produce the overall protective clinical outcomes. While the prophylactic vaccinations could be the most effective and rational medical preventive strategies, their systemic immunity and effectiveness against cancer is debatable. The elaborate epitopic targets of cancer seem to have limited prospects and therapeutic cancer vaccination is an area of questionable efficacy for immunotherapy and safety.
Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients.
Targeting genetic mutations in site‑specific solid cancers that produced repeatedly failed outcomes.
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed.
Prohibitive costs of cancer therapy with repeatedly failed outcomes.
Development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers.
While the goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal, resulting in the failure of cancer vaccines.
Despite the FDA approval of a DC-focused cell-based vaccine, sipuleucel-T, more than 10 years ago, no other therapeutic cancer vaccine has been approved. It is now appreciated that tumour cell intrinsic resistance and local or systemic immunosuppressive (extrinsic) mechanisms substantially compromise the efficacy of cancer vaccines (pg 361, col. 1). This led to a general disappointment in cancer vaccines after it was found that treatment with sipuleucel-T conferred only a small survival advantage in patients with prostate cancer. Moreover, a series of large phase III cancer vaccine studies in advanced disease reported negative outcomes.
Claims 111-112 suffer from failing to recite one or more essential elements, resulting in a gap between the necessary and sufficient method step parameters and the phenotypic results to thereby provide the nexus between “stimulates an immune response” and “treating”, and overcoming the deficiencies of the scientific community. See MPEP §2172.01.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses (pg 69-71 and 73) the pharmaceutical composition may treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan.
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025)
The specification also discloses (pg 70) the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters.
If there are multiple ways to measure “therapeutically effective dose”, then the claim may be indefinite because it is unclear which method step parameter(s) is/are to be performed, individually and/or in combination and/or subcombination thereof, and to achieve which phenotypic result(s) to determine infringement.
The claims encompass a genus of unrecited phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the RNA dosage administered is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
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 claims.
Response to Arguments
Applicant argues that cancellation of the prior Claims 48-49, 73, 75, and 80-81 render the rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s argument is not on point, and does not address the substantive issues of the previously 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection, now applied to the newly presented Claims 111-112.
Applicant argues that the specification provides guidance for the administration routes and determining dosages.
Applicant’s argument(s) has been fully considered, but is not persuasive. 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).
6. Claims 111-112 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 111-112 recite methods of treating ovarian cancer in a human subject, the method comprising the step of administering to the subject a composition comprising at least one RNA encoding a CLDN6 polypeptide, a p53 polypeptide, and a PRAME polypeptide.
The claim denotes that not all pharmaceutical compositions comprising the at least one RNA encoding:
i) a CLDN6 polypeptide at least 95% identical to SEQ ID NO:1;
ii) a p53 polypeptide at least 95% identical to SEQ ID NO:4; and
iii) a PRAME polypeptide at least 95% identical to SEQ ID NO:8; and/or
not all dosages of said RNA pharmaceuticals (Claim 111, dependent upon Claim 90); and/or
not all pharmaceutical compositions comprising the at least one RNA encoding:
i) a CLDN6 polypeptide identical to SEQ ID NO:1;
ii) a p53 polypeptide identical to SEQ ID NO:4; and
iii) a PRAME polypeptide identical to SEQ ID NO:8; and/or
not all dosages of said RNA pharmaceuticals (Claim 112, dependent upon Claim 108);
will necessarily yield the functional property of “treating ovarian cancer”.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
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).
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the RNAs expressing the CLDN6, p53, and PRAME polypeptides must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the structure(s) of CLDN6, p53, and PRAME polypeptides [parameter 4]; and
the phenotypic response to be achieved [parameter 5].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are directed to the treatment of humans.
Parameter 2
The claims are directed to intravenous administration of the RNA pharmaceutical composition.
Parameter 3
The claimed methods are recited at a high level of generality for the RNA dosage that is to be administered. The specification discloses (pg 70) that the “effective amount” will depend on the dose; however, the claims fail to recite, and the specification fails to disclose, the RNA dosage.
Parameter 4
The claimed methods are broad for reciting an enormously vast genus of structurally and functionally undisclosed:
CLDN6 polypeptide variants;
P53 polypeptide variants; and
PRAME polypeptide variants.
The RNA composition of Claim 90, per Claim 111, is broad for encompassing 95% identity to the amino acid sequences of SEQ ID NO’s: 1, 4, and 8, respectively.
CLDN6 SEQ ID NO:1 is 220 amino acids, and thus 95% allows for 11 insertions, deletions, and/or substitutions, yielding a genus of about 2x10^12 structurally undisclosed variants.
P53 SEQ ID NO:4 is 393 amino acids, and thus 95% allows for 20 insertions, deletions, and/or substitutions, yielding a genus of about 1x10^26 structurally undisclosed variants.
PRAME SEQ ID NO:8 is 509 amino acids, and thus 95% allows for 25 insertions, deletions, and/or substitutions, yielding a genus of about 3x10^32 structurally undisclosed variants.
(www.calculator.net/exponent-calculator.html; last visited April 21, 2026)
Thus, the breadth of the claims encompass an enormously vast genus of about 3x10^32, 1x10^26, and/or 2x10^12 structurally and functionally undisclosed polypeptide variants.
Fritsch et al (U.S. 2018/0153975) is considered relevant prior art for having disclosed that tumor antigen epitopes may be as many as 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length (e.g. [0018, 30, 54]).
Those of ordinary skill in the art would immediately recognize that the presence of one or more amino acid deletions, insertions, and/or substitutions encompassed by the instant claims will generate an immune response (syn. antibody formation) directed to one or more epitopes not present in the human subject, thereby negativing the corresponding therapeutic response to the RNA composition.
For example, CLDN6 epitope TCVEEKDSKARLVLT present in SEQ ID NO:1 comprising one or more mutations:
TCV*EKDSKARLVLT
TCV*EKDSKAR*VLT
TCVE*DSKARLV*T
T*VEKDS*ARL*LT
For example, P53 epitope AIYKQSQHMTEV present in SEQ ID NO:4 comprising one or more mutations:
AIY*QSQHMTEV
AIYK*SQH*TEV
AI*KQSQHMT*V
AIY*Q*Q*MTEV
For example, PRAME epitope GVLMKGQHLHLET present in SEQ ID NO:8 comprising one or more mutations:
GVL*KGQHLHLET
G*LMKG*HLHLET
GVLM*GQHL*LET
GV*MKG*HL*LET
The claims fail to recite, and the specification fails to disclose, a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevents metastasis [parameter 5], in a human subject, as opposed to
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. delay tumor development, but is not able to prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is not able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. reduce tumor size [parameter 5], in a human subject, into
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is now able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
Rather, at best, the specification is directed to:
i) a first CLDN6 polypeptide identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide identical to SEQ ID NO:8 [parameter 4].
Example 1 (pg 83) is merely prophetic, and fails to disclose the working dosage to be administered to the human subject.
While pg 126 and Table 10 disclose administration to Cynomolgus monkeys a dosage of 354ug total RNA, upon which no abnormal signs of intolerance was observed, said RNAs are not disclosed to encode CLDN6, P53, and/or PRAME, nor is it disclosed that this dosage was able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
The specification fails to disclose the dosage(s) of RNA pharmaceutical encoding:
i) a CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
The specification fails to disclose the dosage(s) of RNA pharmaceutical encoding:
i) a CLDN6 polypeptide identical to SEQ ID NO:1 in combination with;
ii) a p53 polypeptide identical to SEQ ID NO:4 in combination with; and
iii) a PRAME polypeptide identical to SEQ ID NO:8 [parameter 4],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
CLDN6 SEQ ID NO:1 is 220 amino acids, and thus 95% allows for 11 insertions, deletions, and/or substitutions, yielding a genus of about 2x10^12 structurally undisclosed variants.
P53 SEQ ID NO:4 is 393 amino acids, and thus 95% allows for 20 insertions, deletions, and/or substitutions, yielding a genus of about 1x10^26 structurally undisclosed variants.
PRAME SEQ ID NO:8 is 509 amino acids, and thus 95% allows for 25 insertions, deletions, and/or substitutions, yielding a genus of about 3x10^32 structurally undisclosed variants.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of structurally undisclosed CLDN6, P53, and/or PRAME fragments thereof that will necessarily and predictably have the functional properties of being immunogenic so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic response to treat, prevent, or reduce severity of ovarian cancer, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan in the enormous genus of about 1x10^6 different animal species, including humans.
In sharp contrast, Applicant has disclosed only one species for each polypeptide, respectively, to wit:
1) RNA drug product RBL005.2 (Figure 1) encoding CLDN6 comprising the amino acid sequence of SEQ ID NO:1 (220 amino acids);
2) RNA drug product RBL008.1 (Figure 1) encoding p53 comprising the amino acid sequence of SEQ ID NO:4 (393 amino acids; and
3) RNA drug product RBL012.1 (Figure 1) encoding PRAME comprising the amino acid sequence of SEQ ID NO:8 (509 amino acids).
The Examiner notes that the RNA drug products minimally comprise a 5’ cap, a 5’ UTR sequence, a 3’ UTR sequence, and a polyA sequence (Figure 1), each of which are important structural features that affect the stability and translation of the encoded CLDN6, p53 and PRAME polypeptides, respectively, limitations not recited in the RNA molecules of the independent claim(s).
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claims also denote that there is an amount (syn. dosage) of the RNAs that upon administration to the subject is ineffective or unable to achieve a therapeutic effect.
An (therapeutically) effective amount to do what?
While it is clear the method is to stimulate an immune response, there is a gap in the nexus of “stimulates an immune response” and “treating”.
As discussed below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection, recent attempts on extensive trials of cancer vaccines, using viral structures or substructures against several cancers such as cervices, prostate, lung, pancreatic and skin also failed to produce the overall protective clinical outcomes. While the prophylactic vaccinations could be the most effective and rational medical preventive strategies, their systemic immunity and effectiveness against cancer is debatable. The elaborate epitopic targets of cancer seem to have limited prospects and therapeutic cancer vaccination is an area of questionable efficacy for immunotherapy and safety.
Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients.
Targeting genetic mutations in site‑specific solid cancers that produced repeatedly failed outcomes.
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed.
Prohibitive costs of cancer therapy with repeatedly failed outcomes.
Development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers.
While the goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal, resulting in the failure of cancer vaccines.
Despite the FDA approval of a DC-focused cell-based vaccine, sipuleucel-T, more than 10 years ago, no other therapeutic cancer vaccine has been approved. It is now appreciated that tumour cell intrinsic resistance and local or systemic immunosuppressive (extrinsic) mechanisms substantially compromise the efficacy of cancer vaccines (pg 361, col. 1). This led to a general disappointment in cancer vaccines after it was found that treatment with sipuleucel-T conferred only a small survival advantage in patients with prostate cancer. Moreover, a series of large phase III cancer vaccine studies in advanced disease reported negative outcomes.
Amended Claim 48 suffers from failing to recite one or more essential elements, resulting in a gap between the necessary and sufficient method step parameters and the phenotypic results to thereby provide the nexus between “stimulates an immune response” and “treating”, and overcoming the deficiencies of the scientific community. See MPEP §2172.01.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses (pg 69-71 and 73) the pharmaceutical composition may treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan.
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025; of record)
The specification also discloses (pg 70) the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters.
If there are multiple ways to measure “therapeutically effective dose”, then the claim may be indefinite because it is unclear which method step parameter(s) is/are to be performed, individually and/or in combination and/or subcombination thereof, and to achieve which phenotypic result(s) to determine infringement.
The claims encompass a genus of unrecited phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the RNA dosage administered is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
While the specification discloses a working example whereby RNA drug products RBL005.2, RBL008.1 and RBL012.1 are able to induce an antigen-specific immune response in mice (e.g. pg 107, 109), the specification is silent to the ability of said RNA drug products to prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan.
Rather, such are merely prophetic and hypothetical phenotypic responses to the RNA drug products.
The claims fail to recite, and the specification fails to disclose, a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevents metastasis [parameter 5], in a human subject, as opposed to
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. delay tumor development, but is not able to prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is not able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. reduce tumor size [parameter 5], in a human subject, into
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is now able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
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 CLDN6 polypeptide comprises the amino acid sequence of SEQ ID NO:1 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of RNA molecules encoding the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, individually and/or in combination with;
the initial P53 polypeptide comprises the amino acid sequence of SEQ ID NO:4 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of RNA molecules encoding the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, individually and/or in combination with;
the initial PRAME polypeptide comprises the amino acid sequence of SEQ ID NO:8 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of RNA molecules encoding the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively.
Furthermore, the claims fail to recite, and the specification fails to disclose, the structure(s)/therapeutic function(s) nexus between:
the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat ovarian cancer in a human subject/patient.
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 seeks to claim for themselves:
an enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
an enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
an enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat ovarian cancer in a human subject/patient.
“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.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the structure(s)/therapeutic function(s) nexus between:
the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat ovarian cancer in a human subject/patient.
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.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
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 claims.
Response to Arguments
Applicant argues that the specification discloses the ability to stimulate an immune response in mouse subject upon administration an RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or an RNA encoding PRAME peptide(422-430) ALQSLLQHL (SEQ ID NO:24) (e.g. pg 19, Figure 19 legend; pg 109).
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, the claims neither recite nor requires an RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or an RNA encoding PRAME(422-430) peptide ALQSLLQHL (SEQ ID NO:24). Rather, the claim encompasses the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants thereof, individually and/or in combination with;
the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants thereof, individually and/or in combination with;
the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants thereof.
For example, instead of the argued CLDN6 peptide LVALFGLLVYLAG, the claims reasonably encompass embodiments such as:
LVAL*GLLV*LAG,
LVA*FGLLVY*AG,
LV*LFGL*VYLAG, or
LVALF**LVYLAG.
For example, instead of the argued PRAME peptide ISALQSLLQHLIG, the claims reasonably encompass embodiments such as:
ISAL*SLL*HLIG,
ISA*QSLLQ*LIG,
ISALQ*L*QHLIG, or
ISALQ*LL*HLIG.
As a second matter, nowhere in the specification is it disclosed what the dosage of said RNAs was administered to the mouse subject.
As a third matter, nowhere in the specification is it disclosed that the thus-administered RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or the thus-administered RNA encoding PRAME peptide(422-430) ALQSLLQHL (SEQ ID NO:24) is able to achieve a real-world, clinically meaningful therapeutic result, including, but not limited to, the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, thereby treating ovarian cancer in a mouse subject, let alone the claimed human subject/patient.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“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 is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
7. Claims 111-112 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
Considering the mode of administration, the specification simply requires administration of the RNA(s) to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013; of record) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016; of record) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
The claims fail to recite, and the specification fails to disclose, a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevents metastasis [parameter 5], in a human subject, as opposed to
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. delay tumor development, but is not able to prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first RNA encoding:
i) a first CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a first p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a first PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is not able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. reduce tumor size [parameter 5], in a human subject, into
a second RNA encoding:
i) a second CLDN6 polypeptide variant of the about 2x10^12 structurally undisclosed variants at least 95% identical to SEQ ID NO:1 in combination with;
ii) a second p53 polypeptide the about 1x10^26 structurally undisclosed variants at least 95% identical to SEQ ID NO:4 in combination with; and
iii) a second PRAME polypeptide variant of the about 3x10^32 structurally undisclosed variants at least 95% identical to SEQ ID NO:8 [parameter 4],
and corresponding first dosage(s) thereof [parameter 3],
that is now able to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of ovarian cancer, e.g. prevent metastasis and/or reduce tumor growth [parameter 5], in a human subject, for example.
While the specification discloses a working example whereby RNA drug products RBL005.2, RBL008.1 and RBL012.1 are able to induce an antigen-specific immune response in mice (e.g. pg 107, 109), the specification is silent to the ability of said RNA drug products to prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan.
Rather, such are merely prophetic and hypothetical phenotypic responses to the RNA drug products.
The specification fails to make up for deficiencies of the global scientific community, and thus the ordinary artisans must determine for themselves that which Applicant fails to disclose.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to formulate a pharmaceutical composition comprising:
the enormous genus of unrecited and undisclosed RNA doses of the enormously vast genus of RNA molecules encoding the enormously vast genus of about 2x10^57 and/or about 1x10^143 structurally and functionally undisclosed immunogenic CLDN6 polypeptide variants, and the about 3x10^32 structurally and functionally undisclosed fragments thereof, respectively;
the enormous genus of unrecited and undisclosed RNA doses of the enormously vast genus of RNA molecules encoding the enormously vast genus of about 2x10^256 and/or about 6x10^102 structurally and functionally undisclosed immunogenic P53 polypeptide variants, and the about 3x10^32 structurally and functionally undisclosed fragments thereof, respectively; and
the enormous genus of unrecited and undisclosed RNA doses of the enormously vast genus of RNA molecules encoding the essentially infinite(!) and/or enormously vast genus of about 5x10^132 structurally and functionally undisclosed immunogenic PRAME polypeptide variants, and the about 3x10^32 structurally and functionally undisclosed fragments thereof, respectively,
and administer said pharmaceutical composition via the corresponding enormous genus of anatomically distinct administration routes, including, but not limited to delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic,
so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result treating ovarian cancer, wherein said therapeutic result includes, but is not limited to, the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
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 seeks to claim for themselves:
an enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
an enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
an enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat ovarian cancer in a human subject/patient.
“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.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the structure(s)/therapeutic function(s) nexus between:
the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, individually and/or in combination with;
the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants, respectively, and structurally undisclosed corresponding dosages thereof, and
the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat ovarian cancer in a human subject/patient.
The instant claims and specification fail to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Maeda et al (Analyses of repeated failures in cancer therapy for solid tumors: poor tumor‑selective drug delivery, low therapeutic efficacy and unsustainable costs, Clinical and Translational Medicine 7: e11, 20 pages, doi.org/10.1186/s40169-018-0185-6; available online March 1, 2018; of record) is considered relevant prior art for having taught that recent immunotherapy for solid tumors (e.g. ovarian cancer) produced outcome failure-rates of 90% (Abstract). Despite the initial enthusiasm for site-specific cancer, the outcomes are bleak and disappointing. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. Other recently published articles on basic research and clinical studies of cancer and pathogen-specific vaccines have raised serious concerns about the worthiness, hidden agenda and high costs of these reductionist approaches to such projects that are toxic and repeatedly failed the public (pg 2, col. 1).
While the isolated molecular entities (e.g. CLDN6, P53, PRAME) are parts of the highly heterogeneous and chaotic landscape in cancer biology, they should not be considered as ‘target’ for therapy as they have little/no value on their own for translational purposes although they may work in mouse models for the selected conditions and duration of therapy which do not apply to human (e.g. pg 2, col’s 1-2, joining para).
The decision makers of such expensive, out-of-focus and fuzzy
undertakings seldom consider the life-threatening consequences of wrong and reductionist approaches to drug development for patients and the tremendous economic burden to the society. The irresponsible decision makers of such undertakings, either abandon data on failed outcomes or downplay and ignore the serious consequences of drugs (pg 2, col. 2).
Recent attempts on extensive trials of cancer vaccines, using viral structures or substructures against several cancers such as cervices, prostate, lung, pancreatic and skin also failed to produce the overall protective clinical outcomes. While the prophylactic vaccinations could be the most effective and rational medical preventive strategies, their systemic immunity and effectiveness against cancer is debatable. The elaborate epitopic targets of cancer seem to have limited prospects and therapeutic cancer vaccination is an area of questionable efficacy for immunotherapy and safety (pg 3, col. 2).
As recently reported, a closer look at cancer science reveals that highly powered structure (hierarchy) in cancer/medical establishment (system) versus antisystem and chaotic approaches to cancer research and therapy (‘medical/scientific ponzi schemes’) are potent recipes for failed therapeutics that kills patients but generates huge corporate profit (pg 4, col. 1). Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients. In these studies, little considerations are given to the cellular immune composition of site-specific tissues, the immune-non-immune local or systemic compensatory response mechanisms, the bioenergetics and oxido redox profiles of tissues toward checkpoint inhibition, as well as, the host immune and non-immune interactions with recruited cells and the adverse responses that are observed following therapy (pg 4, col. 1).
Targeting genetic mutations in site‑specific solid cancers that produced repeatedly failed outcomes while generated huge corporate profits. Molecular target drugs created great business motives for drug industry to focus on them in the last six decades. After revealing extremely high incidence of mutations in solid cancer, very little scientific rationale has been presented for developing such costly molecular target drugs that are based on identification of too many evolving genetic mutations in the chaotic cancer environments (pg 5, col. 2). Ovarian cancers may comprise as many as 30-60 different mutations (Table 1).
Evaluation of some drug encapsulated liposomes and micellar nanoparticles reveal another example of failed attempts in cancer chemotherapy. Nanotechnology-based nanomedicine has been the focus of great attention in the past couple of decades. Initially, liposome particles presented the poorest outcomes in the pharmacokinetics because of little considerations of the rapid clearance and removal of nanoparticles by phagocytic cells (pg 9, col. 2).
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed (pg 10, col. 2).
Prohibitive costs of cancer therapy with repeatedly failed outcomes. Economic impact on medical insurance, and unbearable burden to the society. A serious problem in current cancer chemotherapy involves the cost of care for cancer patients, particularly the astronomical costs of recently claimed molecular ‘targeted’ drug, ‘personalized’ or ‘precision’ medicine with outcome failure rates of 85–95%. While majority of such drugs produced no reasonable benefit to meaningfully extend survival of cancer patients, particularly those with solid tumors, they are tremendously costly for the patients, their families and the public (pg 13).
Concerned voices of independent and competent professionals, oncologists and scientists that are raised for seeking the truth in cancer science, on behalf of the cancer-stricken public for changing the directions in cancer research or therapy or safety and unethical motives behind development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers. We also suggested that the USA policy makers and medical/cancer establishment to return to ‘common sense’ that our forefathers used to serve the public (pg 14, col. 1).
Saxena et al (Therapeutic Cancer Vaccines, Nature Reviews 21: 360-378, June 2021; of record) is considered relevant post-filing art for having taught that the goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal, resulting in the failure of cancer vaccines (Abstract). The aim of therapeutic cancer vaccines is to stimulate the patient’s adaptive immune system against specific tumour antigens to regain control over tumour growth, induce regression of established tumours and eradicate minimal residual disease. The basic principles needed for successful therapeutic vaccination against tumours include delivery of large amounts of a high-quality antigen to DCs, optimal DC activation, induction of strong and sustained CD4+ T helper cell and cytotoxic T lymphocyte (CTL) responses, infiltration of the TME and durability and maintenance of response (pg 360, col. 2).
Despite the FDA approval of a DC-focused cell-based vaccine, sipuleucel-T, more than 10 years ago, no other therapeutic cancer vaccine has been approved. It is now appreciated that tumour cell intrinsic resistance and local or systemic immunosuppressive (extrinsic) mechanisms substantially compromise the efficacy of cancer vaccines (pg 361, col. 1). This led to a general disappointment in cancer vaccines after it was found that treatment with sipuleucel-T conferred only a small survival advantage in patients with prostate cancer. Moreover, a series of large phase III cancer vaccine studies in advanced disease reported negative outcomes. The complex set of host, tumour and environmental factors was not appreciated to have such a direct impact on tumour-specific immunity, and the design of cancer vaccines did not take into account all the mechanisms governing immune ignorance, exclusion, suppression and escape. Consequently, these vaccines failed to generate the numbers of T cells or the durability of the T cell response required to elicit long-lasting immunity, making it evident that new strategies are required to overhaul the field’s approach to vaccine therapy. (pg 362, col. 1).
An obvious reason for the failure of cancer vaccines appears to be the choice of less immunogenic vaccine platforms or antigens, on the basis of the low percentage (11–50%) of patients showing a response to vaccination or the induction of non-effective allo-HLA-specific immune responses when allogeneic cell vaccines were used (pg 362, col. 2).
Additional issues regarding neoantigen vaccines include screening antigens for maximal clinical efficacy before vaccination, the number of neoepitopes to include in each vaccine and at what dosage, minimizing the lengthy vaccine production pipeline (currently around 3 months), the delivery platform, combination with ICI or other modalities and overcoming secondary mechanisms of resistance (pg 363, col. 2).
A big challenge in the field of therapeutic cancer vaccinology is ensuring the delivery of vaccine components to the appropriate compartment, be it the tumour-proximal secondary lymphoid organ or the TME. The anatomic location of the tumour, the baseline TME immune landscape, the mechanism of action of the vaccine and the biochemical properties of the vaccine components all need to be cumulatively considered before the best-suited delivery platform can be determined (pg 365, col. 1). Key determinants of antigen vaccine success appear to be (1) the type of antigens (MHC-I or MHC-II restricted), (2) the antigen dosing, (3) the adjuvant used and (4) the administration route (pg 365, col. 2).
Instant claims and specification fail to make up for the deficiencies of the global scientific community.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014; of record) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017; of record) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020; of record) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; of record) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The instant claims and specification fail to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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 claims.
Response to Arguments
Applicant argues that the specification discloses the ability to stimulate an immune response in mouse subject upon administration an RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or an RNA encoding PRAME(422-430) peptide ALQSLLQHL (SEQ ID NO:24) (e.g. pg 19, Figure 19 legend; pg 109).
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, the claims neither recite nor require an RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or an RNA encoding PRAME peptide(422-430) ALQSLLQHL (SEQ ID NO:24). Rather, the claim encompasses the enormously vast genus of about 2x10^12 structurally and functionally undisclosed CLDN6 variants thereof, individually and/or in combination with;
the enormously vast genus of about 1x10^26 structurally and functionally undisclosed P53 polypeptide variants thereof, individually and/or in combination with;
the enormously vast genus of about 3x10^32 structurally and functionally undisclosed PRAME polypeptide variants thereof.
As a second matter, nowhere in the specification is it disclosed what the dosage of said RNAs was administered to the mouse subject.
As a third matter, nowhere in the specification is it disclosed that the thus-administered RNA encoding CLDN6(91-99) peptide ALFGLLVYL (SEQ ID NO:23) or the thus-administered RNA encoding PRAME peptide(422-430) ALQSLLQHL (SEQ ID NO:24) is able to achieve a real-world, clinically meaningful therapeutic result, including, but not limited to, the enormous genus of physiologically different therapeutic results, including but not limited to, treat, prevent, or reduce severity of a disease/disorder, inhibition of the disease course, slows disease progress, interrupting or reversing disease progress, delay onset or prevent onset of disease, decrease tumor growth, shrink tumor/lesion, increase a human subject’s immune response to a tumor, reduce/delay/ameliorate/prevent tumor growth, size, and/or metastasis, inhibit/retard/slow some extent of, or may stop, cancer cell infiltration into peripheral organs, prevent or delay occurrence and/or recurrence of tumor, relieve to some extent one or more symptoms associated with cancer, and/or improves health status and/or prolongs or increases lifespan, whereby the “effective amount” will depend on the condition to be treated, the severeness of disease, individual parameters of the patient, including age, physiological condition, size and weight, duration of treatment, type of accompanying therapy, specific route of administration, and dose, each of which are variable parameters, thereby treating ovarian cancer in a mouse subject, let alone the claimed human subject/patient.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“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 is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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.
Product claims
8. Claims 90, 99, 106-109, and 115-116 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Sahin et al (WO 13/143683; Applicant’s own work; of record in ISR; hereafter Sahin-1; of record) in view of Sahin et al (WO 15/014375; Applicant’s own work; of record in ISR; hereafter Sahin-2), Sahin et al (available online July 13, 2017; Applicant’s own work; not cited in an IDS; hereafter Sahin-3; of record), GenBank P56747.2 (human CLDN6, 2017; of record), GenBank AFN61604.1 (human p53, 2012; of record), and GenBank P78395.1 (human PRAME, 2017; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Sahin-1 is considered relevant prior art for having disclosed RNA molecules for immunotherapy (e.g. pg 2, last para; pg 14, para 1), wherein said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence (e.g. pg 18, para 1).
Sahin-2 is considered relevant prior art for having disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Neither Sahin-1, -2, nor -3 teach/disclose wherein: the CLDN6 polypeptide comprises the amino acid sequence of SEQ ID NO:1;
the P53 polypeptide comprises the amino acid sequence of SEQ ID NO:4; and/or
the PRAME polypeptide comprises the amino acid sequence of SEQ ID NO:8.
However, prior to the effective filing date of the instantly claimed invention,
GenBank P56747.2 is considered relevant prior art for having taught a human CLDN6 polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:1.
GenBank AFN61604 is considered relevant prior art for having taught a human P53 polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:4.
GenBank P78395.1 is considered relevant prior art for having taught a human PRAME polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:8.
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 and the design and synthesis of RNA vaccines. 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 modify the RNA tumor antigen vaccine of Sahin-1 encoding a Claudin 6 immunogenic amino acid sequence to further comprise a p53 immunogenic amino acid sequence and a PRAME immunogenic amino acid sequence with a reasonable expectation of success because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Applicant themselves (Sahin-2; Sahin-3) disclosed and successfully reduced to practice the ability to synthesize an RNA vaccine encoding immunogenic amino acid sequences from at least two, three, or five tumor-associated antigens.
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 RNA encoding CLDN6 with a second RNA encoding CLDN6 comprising the amino acid sequence of SEQ ID NO:1 and/or a first RNA encoding P53 with a second RNA encoding P53 comprising the amino acid sequence of SEQ ID NO:4 and/or a first RNA encoding PRAME with a second RNA encoding PRAME comprising the amino acid sequence of SEQ ID NO:8 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 RNA encoding CLDN6 with a second RNA encoding CLDN6 comprising the amino acid sequence of SEQ ID NO:1 and/or a first RNA encoding P53 with a second RNA encoding P53 comprising the amino acid sequence of SEQ ID NO:4 and/or a first RNA encoding PRAME with a second RNA encoding PRAME comprising the amino acid sequence of SEQ ID NO:8 because those of ordinary skill in the art previously recognized SEQ ID NO:1, SEQ ID NO:4, and SEQ ID NO:8 to be the amino acid sequences of human CLDN6, P53, and PRAME, respectively.
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 99, Sahin-1 disclosed wherein each of the CLDN6, p53, and PRAME amino acids are encoded by a separate RNA, e.g. “RNA encoding an antigen [singular]…results in expression of said antigen [singular]” (pg 33, para 3).
Sahin-2 disclosed wherein the RNA may be polyepitopic (e.g. pg 42, para 3).
Sahin-3 taught wherein the RNA encoded multiple antigens (e.g. Figure 1b).
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 would have immediately recognized that there are only two options, either the antigens are encoded on the same RNA molecule or different RNA molecules, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success.
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 and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
With respect to Claim 106, Sahin-1 disclosed wherein the RNA comprises a polyA sequence (e.g. pg 31, para 2).
Sahin-2 disclosed wherein the RNA comprises a polyA sequence (e.g. pg 35, para 4).
Sahin-3 taught wherein the RNA comprises a polyA sequence (e.g. Figure 1b).
With respect to Claims 107, Sahin-1 disclosed wherein the RNA is formulated as lipoplex nanoparticles (syn. liposomes; e.g. pg 34, para 4).
Sahin-2 disclosed wherein the RNA is formulated as lipoplex nanoparticles (syn. liposomes; e.g. pg 39, last para).
Sahin-3 taught wherein the RNA is formulated as a liquid and/or solid (e.g. determination of concentration, pH, osmolality; “diluted in Ringer’s solution”, Supplemental Methods).
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The phrase “for intravenous administration” is an intended use limitation, which does not contain any further structural limitations with respect to claimed pharmaceutical composition (see MPEP §2114).
With respect to Claims 115-116, Sahin-1 disclosed wherein the RNA is formulated with a pre-formed liposomal formulation (e.g. Example 1, pgs 62-63; pg 64, “RNAs and Liposomes were prediluted…in buffer…prior to mixing”), which is considered to fulfill a “kit”, wherein said kit comprises a first container comprising the liposomal formulation and a second container comprising the RNA.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the number of possible unordered combinations of three tumor-associated antigens listed by Sahin-1 (82 tumor antigens) does not reasonably lead to the instantly claimed combination.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, independent Claim 90 recites a “pharmaceutical composition comprising at least one RNA….”. The term "comprising" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). While it is clear that the claimed RNA pharmaceutical composition is to contain an RNA encoding CLDN6, p53, and PRAME, the breadth of the claimed RNA pharmaceutical composition also allows for the additional presence of RNAs encoding many, most, and/or all of the 82 tumor antigens in the list of Sahin-1 (pg 18, para 1). To put it another way, the instant claims fail to omit or otherwise exclude the presence of RNAs encoding the other 79 tumor antigens also disclosed by Sahin-1.
As a second matter, the Examiner also provides the following references to rebut applicant’s arguments regarding the state of the prior art regarding, e.g. selecting a subset combination from a large list of defined, known options. Note: these references are not considered a part of the 103 rejection but are solely provided to rebut applicant’s argument(s).
Dubensky et al (U.S. Patent 9,044,420) is considered relevant prior art for having claimed a pharmaceutical composition comprising a first immunogen in combination with a second immunogen from a defined list of about 160 known options of tumor antigens (e.g. claims 13 and 19), wherein said list comprises P53 and PRAME.
Similarly, June et al (U.S. Patent 11,161,907) is considered relevant art for having claimed a pharmaceutical composition comprising a first polypeptide directed to a first tumor antigen in combination with a second polypeptide directed to a second tumor antigen from a defined list of about 138 known options of tumor antigens (e.g. claims 3), wherein said list comprises CLDN6 and P53.
Patented claims are considered enabled, and predictable with a reasonable expectation of success, absent objective evidence to the contrary.
The specification, e.g. Sahin-1 disclosing CLDN6, P53, and PRAME from a defined list of 82 known options--substantially smaller than the lists of Dubensky et al (list of 160 known tumor antigen options) and June et al (list of 138 known tumor antigen options), need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
Thus, absent objective evidence to the contrary, no undue experimentation is required by the ordinary artisan to arrive at the combination of CLDN6, P53, and PRAME from a defined list of 82 known options.
Applicant provides no objective evidence of record that the ordinary artisan was/is absolutely prohibited from arriving at the combination of CLDN6, P53, and PRAME from the defined list of 82 known options previously disclosed by Applicant themselves (Sahin-1) with a reasonable expectation of success.
Applicant argues that Sahin-2 does not disclose p53.
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). Sahin-1 disclosed CLDN6, p53, and PRAME.
Applicant argues that Sahin-2 is primarily focused on breast cancer, not ovarian cancer.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant claims are directed to a product, not a method of use.
As a second matter, Applicant themselves (Sahin-2; Sahin-3) disclosed and successfully reduced to practice the ability to synthesize an RNA vaccine encoding immunogenic amino acid sequences from at least two, three, or five tumor-associated antigens.
As a third matter, the Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Sahin-2 disclosed the cancer may be breast cancer or ovarian cancer (e.g. pg 46, last para; pg 49, line 5, “ovarian adenocarcinoma”; Figure 5, “ovary”).
The Examiner also provides the following references to rebut applicant’s arguments regarding the state of the prior art regarding, e.g. a nexus between breast cancer and ovarian cancer. Note: these references are not considered a part of the 103 rejection but are solely provided to rebut applicant’s argument(s).
Cotessi et al (The Human EKC/KEOPS Complex Is Recruited to Cullin2 Ubiquitin Ligases by the Human Tumour Antigen PRAME, PLoS ONE 7(8): e42822, doi:10.1371/journal.pone.0042822; available online August 13, 2012) is considered relevant prior art for having taught that those of ordinary skill in the art previously recognized that PRAME is a tumor antigen for both breast cancer and ovarian cancer (e.g. pg 1, col. 1, Introduction).
Feki et al (Mutational spectrum of p53 mutations in primary breast and ovarian tumors, Critical Reviews in Oncology/Hematology 52(2): 103-116, 2004) is considered relevant prior art for having taught that those of ordinary skill in the art previously recognized that P53 is a tumor antigen for both breast cancer and ovarian cancer (e.g. Title).
Wagner (Molecular and functional characterization of the candidate tumor antigens placenta specific 1 and claudin 6, Dissertation, Doctor der Naturwissenshaften, Am Fachbereich Biologie der Johannes Gutenberg Universitat Mainz, doi.org/10.25358/openscience-2827, 2014; Applicant’s own work not cited in an IDS) is considered relevant prior art for having taught that those of ordinary skill in the art previously recognized that P53 is a tumor antigen for both breast cancer and ovarian cancer (e.g. Title).
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, or established scientific principles. 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.
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).
As evidenced by Cotessi et al, Feki et al, and Wagner (Applicant’s own work not cited in an IDS), those of ordinary skill in the art previously recognized the scientific concepts that CLDN6, P53, and PRAME were art-recognized tumor antigens associated with both breast cancer and ovarian cancer.
Applicant does not contest the teachings of GenBank P56747.2 (human CLDN6, 2017), GenBank AFN61604.1 (human p53, 2012), and GenBank P78395.1 (human PRAME, 2017) as applied to the obviousness to substitute a first RNA encoding CLDN6 with a second RNA encoding CLDN6 comprising the amino acid sequence of SEQ ID NO:1 and/or a first RNA encoding P53 with a second RNA encoding P53 comprising the amino acid sequence of SEQ ID NO:4 and/or a first RNA encoding PRAME with a second RNA encoding PRAME comprising the amino acid sequence of SEQ ID NO:8 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 RNA encoding CLDN6 with a second RNA encoding CLDN6 comprising the amino acid sequence of SEQ ID NO:1 and/or a first RNA encoding P53 with a second RNA encoding P53 comprising the amino acid sequence of SEQ ID NO:4 and/or a first RNA encoding PRAME with a second RNA encoding PRAME comprising the amino acid sequence of SEQ ID NO:8 because those of ordinary skill in the are previously recognized SEQ ID NO:1, SEQ ID NO:4, and SEQ ID NO:8 to be the amino acid sequences of human CLDN6, P53, and PRAME, respectively.
Applicant argues that the list of Sahin-1 contains dozens of prospective tumor-associated antigens, and there is no teaching to select the three specific CLDN6, p53, and PRAME.
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).
Sahin-1 disclosed said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence in a defined list (e.g. pg 18, para 1).
The list of 82 tumor-associated antigens is not so great to prohibit the ordinary artisan from envisioning CLDN6, p53, and PRAME as an embodiment. That other tumor-associated antigens are disclosed within the genus does not negate the fact that CLDN6, p53, and PRAME were each specifically disclosed.
Sahin-2 disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
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 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.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Applicant argues that the cited prior art does not teach/disclose a motivation to select and combine CLDN6 with p53 and PRAME with a reasonable expectation of success.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Sahin-1 disclosed said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence in a defined list (e.g. pg 18, para 1).
The list of 82 tumor-associated antigens is not so great to prohibit the ordinary artisan from envisioning CLDN6, p53, and PRAME as an embodiment. That other tumor-associated antigens are disclosed within the genus does not negate the fact that CLDN6, p53, and PRAME were each specifically disclosed.
Sahin-2 disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Each of Sahin-1, -2, and -3 are directed to methods of stimulating an immune response to one or more tumor-associated antigens.
Those of ordinary skill in the art would have immediately recognized that RNAs encoding CLDN6, p53, and PRAME would each stimulate an immune response, respectively, per natural law of biology and immunology.
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 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.
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).
Method claims
9. Claims 92-97 and 113-114 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Sahin et al (WO 13/143683; Applicant’s own work; of record in ISR; hereafter Sahin-1; of record) in view of Sahin et al (WO 15/014375; Applicant’s own work; of record in ISR; hereafter Sahin-2), Sahin et al (available online July 13, 2017; Applicant’s own work; not cited in an IDS; hereafter Sahin-3; of record), GenBank P56747.2 (human CLDN6, 2017; of record), GenBank AFN61604.1 (human p53, 2012; of record), and GenBank P78395.1 (human PRAME, 2017; of record), Kloudova et al (2016; of record in IDS), and Klamp et al (U.S. 2013/0052217; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Sahin-1 is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject having cancer, wherein the cancer may be ovarian cancer (e.g. pg 42, para 2), the method comprising the step(s) of administering to the subject a pharmaceutical composition comprising RNA molecules for immunotherapy (e.g. pg 2, last para; pg 14, para 1), wherein said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence (e.g. pg 18, para 1).
Sahin-2 is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject having cancer, wherein the cancer may be ovarian cancer (e.g. pg 46, last para; pg 49, lines 5-7), the method comprising the step(s) of administering to the subject a pharmaceutical composition comprising RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Neither Sahin-1, -2, nor -3 teach/disclose wherein: the CLDN6 polypeptide comprises the amino acid sequence of SEQ ID NO:1;
the P53 polypeptide comprises the amino acid sequence of SEQ ID NO:4; and/or
the PRAME polypeptide comprises the amino acid sequence of SEQ ID NO:8.
However, prior to the effective filing date of the instantly claimed invention,
GenBank P56747.2 is considered relevant prior art for having taught a human CLDN6 polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:1.
GenBank AFN61604 is considered relevant prior art for having taught a human P53 polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:4.
GenBank P78395.1 is considered relevant prior art for having taught a human PRAME polypeptide whose amino acid sequence is 100% identical to instant SEQ ID NO:8.
Kloudova et al is considered relevant prior art for having taught that PRAME and p53 are art-recognized tumor-associated antigens for ovarian cancer cells (e.g. Abstract).
Similarly, Klamp et al is considered relevant prior art for having disclosed that CLDN6 is an art-recognized tumor-associated antigen for ovarian cancer cells (e.g. [0084]).
Sahin-1 disclosed wherein the RNA formulations are administered intravenously to the subject (e.g. pg 1, para 3; Figure 19 legend; pg 64, para 3).
Sahin-2 disclosed wherein the RNA formulations are administered intravenously to the subject (e.g. pg 54, para 1).
Klamp et al disclosed wherein the nucleic acid vaccine is administered intravenously to the subject (e.g. [0174, 201]).
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 stimulating an immune response in a subject having cancer, e.g. ovarian cancer, comprising the step of administering an RNA tumor antigen vaccine of Sahin-1 encoding a Claudin 6 immunogenic amino acid sequence to further comprise a p53 immunogenic amino acid sequence and a PRAME immunogenic amino acid sequence with a reasonable expectation of success because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Kloudova et al and Klamp et al evidence that those of ordinary skill in the art previously recognized the scientific concepts that CLDN6, p53, and PRAME are art-recognized tumor-associated antigens for ovarian cancer. Applicant themselves previously disclosed the immunotherapy is useful for ovarian cancer. Applicant themselves (Sahin-2; Sahin-3) disclosed and successfully reduced to practice the ability to synthesize an RNA vaccine encoding immunogenic amino acid sequences from at least two, three, or five tumor-associated antigens.
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 97, Sahin-1 disclosed wherein each of the CLDN6, p53, and PRAME amino acids are encoded by a separate RNA, e.g. “RNA encoding an antigen [singular]…results in expression of said antigen [singular]” (pg 33, para 3).
Sahin-2 disclosed wherein the RNA may be polyepitopic (e.g. pg 42, para 3).
Sahin-3 taught wherein the RNA encoded multiple antigens (e.g. Figure 1b).
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 would have immediately recognized that there are only two options, either the antigens are encoded on the same RNA molecule or different RNA molecules, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success.
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 and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
With respect to Claims 92, 96, and 113-114, Sahin-1 disclosed wherein the pharmaceutical composition is administered by injection or intravenous administration (e.g. pg 55, last para).
Sahin-2 disclosed wherein the pharmaceutical composition is administered by injection or intravenous administration (e.g. pg 54, para 1).
With respect to Claim 93, Sahin-1 disclosed wherein the RNA is formulated as lipoplex nanoparticles (syn. liposomes; e.g. pg 34, para 4).
Sahin-2 disclosed wherein the RNA is formulated as lipoplex nanoparticles (syn. liposomes; e.g. pg 39, last para).
Sahin-3 taught wherein the RNA is formulated as a liquid and/or solid (e.g. determination of concentration, pH, osmolality; “diluted in Ringer’s solution”, Supplemental Methods).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Kloudova et al mentions several other tumor antigens not mentioned in Sahin-1, Sahin-2, or Sahin-3.
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).
Sahin-1 disclosed said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence in a defined list (e.g. pg 18, para 1).
The list of 82 tumor-associated antigens is not so great to prohibit the ordinary artisan from envisioning CLDN6, p53, and PRAME as an embodiment. That other tumor-associated antigens are disclosed within the genus does not negate the fact that CLDN6, p53, and PRAME were each specifically disclosed.
Sahin-2 disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Kloudova et al taught that PRAME and p53 are art-recognized tumor-associated antigens for ovarian cancer cells (e.g. Abstract).
Klamp et al disclosed that CLDN6 is an art-recognized tumor-associated antigen for ovarian cancer cells (e.g. [0084]).
Applicant argues that Klamp et al do not mention PRAME or P53, and thus cannot be relied upon the combination claimed.
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).
Sahin-1 disclosed said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence in a defined list (e.g. pg 18, para 1).
The list of 82 tumor-associated antigens is not so great to prohibit the ordinary artisan from arriving at the combination CLDN6, p53, and PRAME as an embodiment. That other tumor-associated antigens are disclosed within the genus does not negate the fact that CLDN6, p53, and PRAME were each specifically disclosed as known options from a defined list.
Sahin-2 disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Kloudova et al taught that PRAME and p53 are art-recognized tumor-associated antigens for ovarian cancer cells (e.g. Abstract).
Klamp et al disclosed that CLDN6 is an art-recognized tumor-associated antigen for ovarian cancer cells (e.g. [0084]).
Applicant argues that Kluodova et al did not assess CLDN6.
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).
Sahin-1 disclosed said RNA molecule encodes a Claudin 6 (CLDN6) immunogenic amino acid sequence, a p53 immunogenic amino acid sequence, or a PRAME immunogenic amino acid sequence in a defined list (e.g. pg 18, para 1).
The list of 82 tumor-associated antigens is not so great to prohibit the ordinary artisan from envisioning CLDN6, p53, and PRAME as an embodiment. That other tumor-associated antigens are disclosed within the genus does not negate the fact that CLDN6, p53, and PRAME were each specifically disclosed.
Sahin-2 disclosed RNA molecules for immunotherapy, wherein said RNA molecule encodes a first tumor antigen immunogenic amino acid sequence in combination with a PRAME immunogenic amino acid sequence (e.g. pg 6, para 1; claims 13-14 and 19).
Sahin-3 successfully demonstrated the ability to synthesize an RNA molecule for tumor vaccination, wherein said RNA encodes immunogenic amino acid sequences from more than one tumor associated antigen protein (e.g. pg 222, col. 2; Suppl Table 1).
Kloudova et al taught that PRAME and p53 are art-recognized tumor-associated antigens for ovarian cancer cells (e.g. Abstract).
Klamp et al disclosed that CLDN6 is an art-recognized tumor-associated antigen for ovarian cancer cells (e.g. [0084]).
Conclusion
10. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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