Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed October 24, 2025.
Amendments
Applicant's response and amendments, filed October 24, 2025, is acknowledged. Applicant has cancelled Claims 1-57 and 59-90, and amended Claim 58, and added new claims, Claims 92-105.
Claims 58 and 91-105 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group V, claim(s) 58 and 91, drawn to method of treating a hemoglobinopathy, the method comprising the step(s) of administering to a patient a composition comprising a small molecule compound, siRNA, shRNA, ASO, miRNA, AMO, or any combination thereof, that reduces WIZ gene expression and/or WIZ protein.
Within Group V, Applicant has elected without traverse the following species, wherein:
vii) the alternative molecule is shRNA, as recited in Claims 58, 91, 95, and 102.
Claims 58 and 91-105 are pending.
Claims 92-94, 96-101, and 103-105 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 58, 91, 95, and 102 are under consideration.
Priority
This application is a 371 of PCT/IB2020/001098 filed on December 16, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/950,048 filed on December 18, 2019 and 62/950,025 filed on December 18, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on September 1, 2022 and October 24, 2025 that have been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
1. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g. pg 174, last line). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
2. Claims 58 and 91 are objected to because of the following informalities:
These claims each identify “WIZ”; however, the claims do not first identify the WIZ gene/protein by its complete name prior to using its acronym. The abbreviation should be spelled out in the first appearance of the claims and should be followed by the abbreviation in parentheses, e.g. antisense oligonucleotide (ASO).
Appropriate correction is required.
See, for example, pg 24, line 25.
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.
3. Claims 58, 91, 95, and 102 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
As a first matter, the claims are considered indefinite for failing to recite a positive process step that refers back to the preamble of the claim, being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted step is a correlation or recapitulation step at the end of the claim which restates the preamble. No step is recited that actually achieves the goal stated in the preamble. The claims do not have a step that clearly relates back to the preamble. It is unclear if and what additional, undisclosed steps are a part of the claimed method and therefore the metes and bounds of the claimed subject matter are unclear. The positively recited action-taking step(s), administering to a patient with a shRNA to reduce WIZ gene expression and/or WIZ protein activity, would appear to not be sufficient to achieve the requirement of the preamble(s) “increasing fetal hemoglobin expression” and/or “treating a hemoglobinopathy”. In order for the claimed method to be definite in terms of the metes and bounds of the invention, the claim must recite a method step that provides for the results of the method as claimed.
The claims suffer a gap in the nexus of the target cell(s) into which the shRNA and/or the vector expressing said shRNA is/are to be introduced, and the results to be achieved per the recited preambles.
The art recognizes, for example, at least 1000 different types of cells just in the human body, e.g. erythrocytes, vascular endothelial cells, hepatocytes, neurons, glial cells, epidermal cells, fat cells, fibroblasts, myocytes, etc…. (List of distinct cell types in the adult human body, wikipedia.org/wiki/List_of_distinct_cell_types_in_the_adult_human_body; last visited June 13, 2024).
Rather, the administration step and target cell(s) is/are recited at a high level of generality.
As a second matter, while it is clear that, in Claim 91, the shRNA is to be administered to a patient, the claim does not require said patient to have a hemoglobinopathy, per the preamble. The claim is considered indefinite for being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01.
Compare/contrast Claim 58, which recites “in a patient, ….to the patient” with instant Claim 91.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
4. Claims 58, 91, 95, and 102 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.
Claim 58 is directed to methods of increasing fetal hemoglobin expression in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
Claim 91 is directed to methods of treating a hemoglobinopathy in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
It is understood that in order to meaningfully increase fetal hemoglobin expression and/or 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 shRNA must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The claims also denote that there is an amount (syn. dosage) of the shRNA that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
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 structure of the shRNA [parameter 2];
the structure of the therapeutic nucleic acid vector encoding said shRNA [parameter 3];
the administration route [parameter 4];
the dosage administered [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
Parameter 1
The specification discloses the “patient” is a “subject”, including, but not limited to, a mammalian subject, more specifically a human subject (e.g. pg 116, lines 24-25).
The claims are broad for reasonably encompassing an enormous genus of vertebrate subjects, including mammalian subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primates, cattle, pigs, horses, sheep, cats, dogs, mice, and rats.
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
As discussed in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections, the claims suffer a gap in the nexus of the target cell(s) into which the shRNA and/or the vector expressing said shRNA is/are to be introduced, and the results to be achieved per the recited preambles.
The art recognizes, for example, at least 1000 different types of cells just in the human body, e.g. erythrocytes, vascular endothelial cells, hepatocytes, neurons, glial cells, epidermal cells, fat cells, fibroblasts, myocytes, etc…. (List of distinct cell types in the adult human body, wikipedia.org/wiki/List_of_distinct_cell_types_in_the_adult_human_body; last visited June 13, 2024).
Parameter 2
The breadth of the claims encompasses shRNA molecules that reduces the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly.
The breadth of the claims encompass nucleotide lengths of at least 10 nucleotides to as many as 6000 nucleotides (e.g. pg 8, lines 18-22).
4x10^6000, ^5000, ^4000, ^3000, ^2000, ^1000, and ^750 are each an infinite genus of structurally and functionally undisclosed shRNAs.
4x10^500 is about 1x10^301.
4x10^250 is about 3x10^150.
4x10^100 is about 1x10^60.
4x10^50 is about 1x10^30.
4x10^25 is about 1x10^15.
(www.calculator.net/exponent-calculator; last visited October 29, 2025).
Thus, the claims reasonably encompass an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly.
Those of ordinary skill in the art would immediately recognize that Applicant simply does not possess infinity.
However, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
Parameter 3
The claimed methods are recited at a high level of generality for type of nucleic acid vectors encoding the shRNA (e.g. pg 10, lines 3-6), said vectors including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles.
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 4
The claimed methods are recited at a high level of generality for the multitude 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 (e.g. High et al (U.S. 2015/0111955, [0077]).
Parameter 5
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 6
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 expression vector that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
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 “treating” encompasses:
i) achieving a particular biological result, which itself is an arbitrary and subjective determination;
ii) alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable;
iii) eliciting a significant decrease in the biological activity or process, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and/or
iv) prevent a disease (e.g. pg 28, line 32- pg 29, line 14).
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)
If there are multiple ways to measure “therapeutically effective dose”, to wit, concentration, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding an shRNA an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in a subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in a subject (Claim 58).
The claims fail to recite, and the specification fails to disclose, a first bacteriophage dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to increase fetal hemoglobin expression in a subject, as opposed to a second bacteriophage dosage administered via a second administration route, e.g. intravenously, that is unable to increase fetal hemoglobin expression in a subject, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intrathecal injection, that is unable to treat a hemoglobinopathy in a subject transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of achieving a real-world, clinically meaningful treatment of a hemoglobinopathy in a subject, for example.
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 claim(s).
5. Claim(s) 58, 91, 95, and 102 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 58 is directed to methods of increasing fetal hemoglobin expression in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
Claim 91 is directed to methods of treating a hemoglobinopathy in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
It is understood that in order to meaningfully increase fetal hemoglobin expression and/or 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 shRNA must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The claims also denote that there is an amount (syn. dosage) of the shRNA that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
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:
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 structure of the shRNA [parameter 2];
the structure of the therapeutic nucleic acid vector encoding said shRNA [parameter 3];
the administration route [parameter 4];
the dosage administered [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
The claims reasonably encompass an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly.
Those of ordinary skill in the art would immediately recognize that Applicant simply does not possess infinity.
Rather, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
Perez-Pinera et al (U.S. 2018/0305719) is considered relevant prior art for having disclosed conception of an shRNA or gRNA (e.g. [0142, 279]) that reduces WIZ gene expression and/or WIZ protein activity (e.g. pg 87, Table 11). However, Lewis et al do not disclose a reduction to practice of an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
Lewis et al (U.S. 2019/0202892) is considered relevant prior art for having disclosed conception of an shRNA (e.g. [0017, 32, 136, 212]) that reduces WIZ gene expression and/or WIZ protein activity (e.g. pg 37, Table 2). However, Perez-Pinera et al do not disclose a reduction to practice of an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding an shRNA an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in a subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in a subject (Claim 58).
At best, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
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 shRNA is to have the functional property of reducing WIZ gene expression and/or WIZ protein activity does not tell you anything at all about:
i) the structure(s) of the infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, 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 [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
a) treating a hemoglobinopathy in a subject (Claim 91); and/or
b) increasing fetal hemoglobin expression in a subject (Claim 58), including, but not limited to, achieving a particular biological result, which itself is an arbitrary and subjective determination, alleviating of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a significant decrease in the biological activity or process, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and/or preventing a disease [parameter 6].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed methods encompass:
i) the structure(s) of the infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, 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 [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
a) treating a hemoglobinopathy in a subject (Claim 91); and/or
b) increasing fetal hemoglobin expression in a subject (Claim 58), including, but not limited to, achieving a particular biological result, which itself is an arbitrary and subjective determination, alleviating of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a significant decrease in the biological activity or process, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and/or preventing a disease [parameter 6].
“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.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding an shRNA an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in a subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in a subject (Claim 58).
At best, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
Those of ordinary skill in the art would immediately recognize that Applicant simply does not possess infinity.
The specification fails to disclose a reduction to practice of administering a shRNA pharmaceutical composition to a subject, thereby achieving a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in said subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in said subject (Claim 58).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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 broadly claimed methods.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
See also the 55 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection below.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
6. Claim(s) 58, 91, 95, and 102 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.
Claim 58 is directed to methods of increasing fetal hemoglobin expression in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
Claim 91 is directed to methods of treating a hemoglobinopathy in a subject, the method comprising the step of administering to the subject a composition comprising an shRNA that reduces WIZ gene expression and/or WIZ protein activity.
It is understood that in order to meaningfully increase fetal hemoglobin expression and/or 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 shRNA must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The claims also denote that there is an amount (syn. dosage) of the shRNA that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
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:
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 structure of the shRNA [parameter 2];
the structure of the therapeutic nucleic acid vector encoding said shRNA [parameter 3];
the administration route [parameter 4];
the dosage administered [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The claims reasonably encompass an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly.
Those of ordinary skill in the art would immediately recognize that Applicant simply does not possess infinity.
Rather, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
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.
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 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) 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) 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 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 (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 shRNA is to have the functional property of reducing WIZ gene expression and/or WIZ protein activity does not tell you anything at all about:
i) the structure(s) of the infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, 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 [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
a) treating a hemoglobinopathy in a subject (Claim 91); and/or
b) increasing fetal hemoglobin expression in a subject (Claim 58), including, but not limited to, achieving a particular biological result, which itself is an arbitrary and subjective determination, alleviating of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a significant decrease in the biological activity or process, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and/or preventing a disease [parameter 6].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed methods encompass:
i) the structure(s) of the infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, 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 [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
a) treating a hemoglobinopathy in a subject (Claim 91); and/or
b) increasing fetal hemoglobin expression in a subject (Claim 58), including, but not limited to, achieving a particular biological result, which itself is an arbitrary and subjective determination, alleviating of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a significant decrease in the biological activity or process, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and/or preventing a disease [parameter 6].
“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.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding an shRNA an infinite and/or enormously vast genus of about 1x10^301, 3x10^150, 1x10^60, 1x10^30, and/or 1x10^15 structurally and functionally undisclosed shRNAs that are to reduce the expression of the WIZ gene and/or WIZ protein activity either directly or indirectly [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in a subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in a subject (Claim 58).
At best, the specification only discloses only four (4) actual anti-WIZ shRNAs, each of 21 nucleotides (e.g. pg 159, Table 7; SEQ ID NO’s: 3196-3199).
Those of ordinary skill in the art would immediately recognize that Applicant simply does not possess infinity.
The specification fails to disclose a reduction to practice of administering a shRNA pharmaceutical composition to a subject, thereby achieving a real-world, clinically meaningful result of:
i) treating a hemoglobinopathy in said subject (Claim 91); and/or
ii) increasing fetal hemoglobin expression in said subject (Claim 58).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) 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) 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) 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) 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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Conclusion
7. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638