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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 19, 2026 has been entered.
Detailed Action
This action is in response to the papers filed February 19, 2026.
Amendments
Applicant's response, filed February 19, 2026, is acknowledged.
Applicant has cancelled Claim 38, amended Claims 1, and withdrawn Claims 3, 7-13, 15-16, and 18-37.
The amendment to the claims filed on February 19, 2026 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status of Claim 1 is (Currently amended).
Claims 1-37 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, claim(s) 1-17 and 38, drawn to a method of treating a pulmonary hypertension in a subject comprising administering to the subject a therapeutically effective amount of a nucleic acid vector, wherein the vector comprises a polynucleotide that encodes SCUBE1 or a functional fragment thereof, the administration resulting in a reduction of a pulmonary arterial hypertension and/or a pulmonary vascular resistance in the subject.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative disease condition is pulmonary arterial hypertension, as recited in Claim 2;
ii) the alternative therapeutic outcome/phenotypic effect is decreases a level of pulmonary arterial pressure, as recited in Claim 14; and
iii) the alternative additional method step is further comprising identifying the subject as having a reduction of SCUBE1 in a plasma sample and/or lung tissue sample relative to a control, as recited in Claim 17.
Claims 1-37 are pending.
Claims 3, 7-16, and 18-37 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-2, 4-6, and 17 are under consideration.
Priority
This application is a 371 of PCT/US2020/059969 filed on November 12, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/934,818 filed on November 13, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
1. Claim(s) 1-2, 4-6, and 17 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 1 has been amended to recite a method of reducing pulmonary hypertension in a human subject, the method comprising the step of administering to the human a therapeutically effective amount of a vector,
wherein the vector comprises a polynucleotide that encodes SCUBE1,
thereby resulting in a reduction of a pulmonary arterial hypertension and/or a pulmonary vascular resistance in the human.
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/function of the therapeutic SCUBE1 polypeptide [parameter 2];
the type of nucleic acid delivery vehicle [parameter 3];
the dosage of the nucleic acid delivery vehicle to be administered [parameter 4]; and
the administration route [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 human subjects.
Parameter 2
The claimed SCUBE1 polypeptide encoded by the nucleic acid is recited at a high level of generality, encompassing amino acid insertions, deletions, and/or substitutions (e.g. pg 10, last para).
The specification discloses an embodiment of full-length SCUBE1 protein composed of the amino acid sequence of SEQ ID NO:1 (363 amino acids).
Amended Claim 1 recites at least 90% homology to SEQ ID NO:1, which allows for as many as 39 amino acid insertions, deletions, and/or substitutions in SEQ ID NO:1.
20^36 (90% identity) = about 6x10^46 structurally and functionally undisclosed variants of SEQ ID NO:1.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Yang et al (U.S. 2009/02643361; of record) is considered relevant prior art for having disclosed that SCUBE proteins are involved in the development of cardiovascular disease, hemostasis, thrombosis, inflammatory disease, bone metabolism disorders, urinary bladder disorders and breast disorders (e.g. Abstract), whereby SCUBE proteins are composed of a multitude of structurally different subdomains (e.g. Figures 1-2). Yang et al disclosed SCUBE fragments may be 8-, 11-, 12-, or 14- amino acids in length, being either hydrophobic in nature, or hydrophilic in nature, being glycosylated, or not glycosylated, and may or may not include a cysteine residue (e.g. [0045]). Yang et al disclosed the protein may have thrombolytic activity, enhance coagulation, dissolve or inhibit formation of thromboses (e.g. [0062-63]), may have anti-inflammatory activity, promote cell-cell interactions, inhibit or promote chemotaxis (e.g. [0068]), may stimulate differentiation of monocytes into osteoclasts, thereby affecting bone metabolism (e.g. [0070]), or may modulate urinary bladder function (e.g. [0072]), for example.
Parameter 3
The claims are broad for encompassing a genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, polymeric nanoparticles, etc… (e.g. pg 17, last para).
Parameter 4
The claims are broad for encompassing a genus of structurally unrecited dosages of the nucleic acid delivery vehicle to be administered, whereby the specification discloses the therapeutic amount may range from 0.1% to 99%/weight of the carrier (e.g. pg 13, last para), and whereby the amount will vary depending on the composition, the disorder or conditions and its severity, the route of administration, time of administration, rate of excretion, drug combination, judgment of the treating physician, dosage form, and the age, weight, general health, sex and/or diet of the subject to be treated, each of which are themselves variable parameters (pg 16, para 1).
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Parameter 5
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct suitable administration routes (e.g. pg 8, para 5), 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]; of record).
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 amendment to Claim 1 reciting at least 90% homology to SEQ ID NO:1 renders the phrase “therapeutically effective amount” definite.
Applicant’s argument(s) has been fully considered, but is not persuasive. The present amendment to Claim 1 does nothing for rendering the phrase “therapeutically effective amount” definite.
As discussed above, 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/function of the therapeutic SCUBE1 polypeptide [parameter 2];
the type of nucleic acid delivery vehicle [parameter 3];
the dosage of the nucleic acid delivery vehicle to be administered [parameter 4]; and
the administration route [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” (syn. sub-therapeutic).
The claims are broad for encompassing a genus of:
an enormously vast genus of about 6x10^46 structurally and functionally undisclosed variants of SEQ ID NO:1;
structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, polymeric nanoparticles, etc… (e.g. pg 17, last para);
structurally unrecited dosages of the nucleic acid delivery vehicle to be administered, whereby the specification discloses the therapeutic amount may range from 0.1% to 99%/weight of the carrier (e.g. pg 13, last para), and whereby the amount will vary depending on the composition, the disorder or conditions and its severity, the route of administration, time of administration, rate of excretion, drug combination, judgment of the treating physician, dosage form, and the age, weight, general health, sex and/or diet of the subject to be treated, each of which are themselves variable parameters (pg 16, para 1); and
a multitude of anatomically distinct suitable administration routes (e.g. pg 8, para 5), 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,
each of which are variable method step parameters that affects what does/does not achieve the recited functional property of “a therapeutically effective amount”.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
2. Claims 1-2, 4-6, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a method of reducing pulmonary hypertension in a human subject, the method comprising the step of administering to the human a therapeutically effective amount of a vector,
wherein the vector comprises a polynucleotide that encodes SCUBE1,
thereby resulting in a reduction of a pulmonary arterial hypertension and/or a pulmonary vascular resistance in the human.
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”.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The 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)
The claim(s) 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” (syn. sub-therapeutic).
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/function of the therapeutic SCUBE1 polypeptide encoded by the nucleic acid [parameter 2];
the type of nucleic acid delivery vehicle [parameter 3];
the dosage of the nucleic acid delivery vehicle to be administered [parameter 4]; and
the administration route [parameter 5].
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Parameter 1
The claims are directed to the treatment of human subjects.
Parameter 2
The claimed SCUBE1 polypeptide, and functional fragment thereof, encoded by the nucleic acid is recited at a high level of generality, encompassing amino acid insertions, deletions, and/or substitutions (e.g. pg 10, last para).
The specification discloses an embodiment of full-length SCUBE1 protein composed of the amino acid sequence of SEQ ID NO:1 (363 amino acids).
Amended Claim 1 recites at least 90% homology to SEQ ID NO:1, which allows for as many as 39 amino acid insertions, deletions, and/or substitutions in SEQ ID NO:1.
20^36 (90% identity) = about 6x10^46 structurally and functionally undisclosed variants of SEQ ID NO:1.
20^18 (95% identity) = about 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1.
(www.calculator.net/exponent-calculator; last visited April 15, 2025; of record)
Thus, the claims encompass an enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1.
Yang et al (U.S. 2009/02643361; of record) is considered relevant prior art for having disclosed that SCUBE proteins are involved in the development of cardiovascular disease, hemostasis, thrombosis, inflammatory disease, bone metabolism disorders, urinary bladder disorders and breast disorders (e.g. Abstract), whereby SCUBE proteins are composed of a multitude of structurally different subdomains (e.g. Figures 1-2). Yang et al disclosed SCUBE fragments may be 8-, 11-, 12-, or 14- amino acids in length, being either hydrophobic in nature, or hydrophilic in nature, being glycosylated, or not glycosylated, and may or may not include a cysteine residue (e.g. [0045]). Yang et al disclosed the protein may have thrombolytic activity, enhance coagulation, dissolve or inhibit formation of thromboses (e.g. [0062-63]), may have anti-inflammatory activity, promote cell-cell interactions, inhibit or promote chemotaxis (e.g. [0068]), may stimulate differentiation of monocytes into osteoclasts, thereby affecting bone metabolism (e.g. [0070]), or may modulate urinary bladder function (e.g. [0072]), for example.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007; of record) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006; of record) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1 to necessarily and predictably achieve a real-world, clinically meaningful treatment of pulmonary arterial hypertension and/or pulmonary vascular resistance in the human subjects encompassed by the claims.
Parameter 3
The claims are broad for encompassing a genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, polymeric nanoparticles, etc… (e.g. pg 17, last para).
Parameter 4
The claims are broad for encompassing a genus of structurally unrecited dosages of the nucleic acid delivery vehicle to be administered, whereby the specification discloses the therapeutic amount may range from 0.1% to 99%/weight of the carrier (e.g. pg 13, last para), and whereby the amount will vary depending on the composition, the disorder or conditions and its severity, the route of administration, time of administration, rate of excretion, drug combination, judgment of the treating physician, dosage form, and the age, weight, general health, sex and/or diet of the subject to be treated, each of which are themselves variable parameters (pg 16, para 1).
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Parameter 5
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct suitable administration routes (e.g. pg 8, para 5), 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]; of record).
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 4] of the enormously vast genus of nucleic acid vectors, e.g. RNA [parameter 3], encoding the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1 [parameter 2] administered via a first administration route, e.g. subcutaneously [parameter 5], to a first human subject [parameter 1], that is necessarily and predictably able to prevent pulmonary arterial hypertension [parameter 6], as opposed to a second dosage [parameter 4] of the enormously vast genus of nucleic acid vectors, e.g. bacteriophage [parameter 3], encoding the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1 [parameter 2] administered via a second administration route, e.g. inhalation [parameter 5], to a second human subject [parameter 1], that is necessarily and predictably able to decrease a level of pulmonary arterial pressure [parameter 6], for example.
While the specification contemplates human and non-human animal models, e.g pgs 51-52, all are merely prophetic. There is no reduction to practice of administering a therapeutically effective amount of a nucleic acid encoding SEQ ID NO:1 to a human or non-human animal subject, thereby achieving a real-world, clinically meaningful therapeutic effect, including, but not limited to, amelioration, reversal, mitigation, and/or prevention of pulmonary arterial hypertension and/or pulmonary vascular resistance and/or decreasing a level of pulmonary arterial pressure.
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 SCUBE1 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 about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1.
Furthermore, the claims fail to recite, and the specification fails to disclose, the nexus between:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
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:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
Rather, Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“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.
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 phrase “therapeutically effective amount” is adequately described because it was presented in the originally filed claims.
Applicant’s argument(s) has been fully considered, but is not persuasive. Said amendment does nothing for the lack of adequate written description for “therapeutically effective amount” and the breadth of the claimed method encompassing:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
Applicant argues that various vectors and administrations are conventional and well-known in the art.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant fails to provide objective evidence establishing the nexus between:
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
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 the instant case, the limitation “a therapeutically effective amount” is claiming the invention using functional language.
While the specification contemplates human and non-human animal models, e.g pgs 51-52, all are merely prophetic. There is no reduction to practice of administering a therapeutically effective amount of a nucleic acid encoding SEQ ID NO:1 to a human or non-human animal subject, thereby achieving a real-world, clinically meaningful therapeutic effect, including, but not limited to, amelioration, reversal, mitigation, and/or prevention of pulmonary arterial hypertension and/or pulmonary vascular resistance and/or decreasing a level of pulmonary arterial pressure.
Rather, Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“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.
3. Claims 1-2, 4-6, and 17 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(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
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 SCUBE1 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 about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1.
Furthermore, the claims fail to recite, and the specification fails to disclose, the nexus between:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
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:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
While the specification contemplates human and non-human animal models, e.g pgs 51-52, all are merely prophetic. There is no reduction to practice of administering a therapeutically effective amount of a nucleic acid encoding SEQ ID NO:1 to a human or non-human animal subject, thereby achieving a real-world, clinically meaningful therapeutic effect, including, but not limited to, amelioration, reversal, mitigation, and/or prevention of pulmonary arterial hypertension and/or pulmonary vascular resistance and/or decreasing a level of pulmonary arterial pressure.
Rather, Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“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.
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.
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.
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 amending the independent Claim 1 to recite at least 90% homology to SEQ ID NO:1 renders the claims enabled.
Applicant’s argument(s) has been fully considered, but is not persuasive. Said amendment does nothing for the lack of adequate written description and enablement for “therapeutically effective amount” and the breadth of the claimed method encompassing:
the enormously vast genus of about the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1;
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
Applicant argues that various vectors and administrations are conventional and well-known in the art.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant fails to provide objective evidence establishing the nexus between:
the broad genus of structurally and functionally different nucleic acid vectors, including, but not limited to, plasmids, transposons, bacteriophages, cosmids, artificial chromosomes, viruses, liposomes, and polymeric nanoparticles;
the enormously vast genus of structurally undisclosed doses of the enormous genus of different nucleic acid vectors encoding the enormously vast genus of about 6x10^46 and/or 2x10^23 structurally and functionally undisclosed variants of SEQ ID NO:1; and
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,
whereby the “therapeutically 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 of reducing a pulmonary arterial hypertension and/or pulmonary vascular resistance in human subjects.
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 the instant case, the limitation “a therapeutically effective amount” is claiming the invention using functional language.
While the specification contemplates human and non-human animal models, e.g pgs 51-52, all are merely prophetic. There is no reduction to practice of administering a therapeutically effective amount of a nucleic acid encoding SEQ ID NO:1 to a human or non-human animal subject, thereby achieving a real-world, clinically meaningful therapeutic effect, including, but not limited to, amelioration, reversal, mitigation, and/or prevention of pulmonary arterial hypertension and/or pulmonary vascular resistance and/or decreasing a level of pulmonary arterial pressure.
Rather, Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“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 argues that Examples 2-6 provide in vitro results.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Example 2 merely discloses RNA sequencing data from tissue cultured BMPR2-mutant iPSC-derived endothelial cells. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Example 3 merely discloses endogenous expression of SCUBE1 in tissue cultured pulmonary arterial endothelial cells. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Example 4 merely discloses that HIF-1alpha can downregulate expression of endogenous SCUBE1 in tissue cultured pulmonary arterial endothelial cells. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Example 5 merely discloses that ability to express an exogenous SCUBE1 transgene in tissue cultured pulmonary arterial endothelial cells. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Example 6 merely discloses that expression of an exogenous SCUBE1 transgene in tissue cultured pulmonary arterial endothelial cells reduced SMAD1/5/9 signaling and increased BMPR2 activation. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Applicant argues that Example 7 is directed to a rodent disease model.
Applicant’s argument(s) has been fully considered, but is not persuasive. Example 7 merely discloses measurement of endogenous SCUBE1 levels in blood plasma and lung tissue homogenates of mice. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Applicant argues that Example 8 is directed to analysis of human patients.
Applicant’s argument(s) has been fully considered, but is not persuasive. Example 8 merely discloses measurement of endogenous SCUBE1 levels in blood plasma in human patients suffering from PAH (pulmonary arterial hypertension) and other cardiopulmonary diseases. Such fails to inform the ordinary artisan as to what does/does not achieve a “therapeutically effective amount” per the enormously vast breadth of the instantly claimed method.
Conclusion
4. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638