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 September 13, 2023.
Amendments
Applicant's response and amendments, filed September 13, 2023, is acknowledged. Applicant has cancelled Claims 2-3, amended Claims 1 and 4-5, and added new claims, Claim 6-7.
Claims 1 and 4-7 are pending and are under consideration.
Priority
This application is a continuation in part of application 16/858,511 filed on April 24, 2020, now abandoned, which is a continuation of PCT/KR2018/011248 filed on September 21, 2018.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). Certified copy of the foreign patent application PCT/KR2018/011248 filed on September 21, 2018, KR 10-2018-0112734 filed on September 20, 2018 and KR-2017-0140190 filed on October 26, 2017 are provided with application 16/858,511.
Certified English translations of KR 10-2018-0112734 filed on September 20, 2018 and KR-2017-0140190 filed on October 26, 2017 are provided with application 16/858,511.
A certified English translation of PCT/KR2018/011248 filed on September 21, 2018, has not been provided.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on August 3, 2023 that has been considered.
The information disclosure statement filed August 3, 2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
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 and 4-7 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 recites the limitation “consisting of the amino acid sequence of SEQ ID NO:1”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO:1 is a nucleic acid sequence, not an amino acid sequence.
Applicant should amend the claim to recite “consisting of the nucleic acid sequence of SEQ ID NO:1”.
2. Claim(s) 5-6 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claims 5-6 recite the broad recitation “administered to the subject” and the claim also recites “a viral genome dosage of 1x10^8 to 1x1x10^10 viral genomes/eye” and “a viral genome dosage of 2.48x10^9 to 1x1x10^10 viral genomes/eye” which is/are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language “viral genomes/eye” is (a) merely exemplary of the remainder of the claim, and therefore administration to the eye is not required, or (b) a required feature step of administering to the eye of the claims.
The term “viral genomes/eye” in Claims 5-6 is a relative term which renders the claim indefinite. Claims 1 and 4-6 are generic to the route of administration by which the rAAV is to be administered to the subject.
While it is clear that in Claims 5-6 that 1x10^8, 2.48x10^9, or up to 1x10^10 viral genomes is/are to become present in the eye of the subject upon administration of the rAAV pharmaceutical composition, the limitation “viral genomes/eye” does nothing to inform the ordinary artisan as to the actual viral genome dosage that is to be administered to the subject via the broadly claimed routes of administration encompassed by the claims, including, but not limited to, subcutaneous injection, intramuscular injection, intraperitoneal injection, inhalation, oral ingestion, etc…, such that 1x10^8, 2.48x10^9, or up to 1x1x10^10 viral genomes will necessarily and predictably be delivered to the eye.
See further discussion below in the 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Rather, see Claim 7 that positively recites “intravitreally administered”.
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
The Examiner suggests amending Claim 5 to recited “is administered to the eye of the subject at a viral genome dosage of…”, or “is administered to the subject’s eye at a viral genome dosage of…”, for example.
3. Claim(s) 1 and 4-7 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 is directed to a method of treating macular degeneration comprising administering an effective amount of a recombinant AAV vector comprising a soluble VEGF receptor variant cDNA to a subject in need thereof.
The claim denotes that there is an amount of the pharmaceutical composition that upon administration to the subject is not, in fact, “a therapeutically effective amount”.
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 human or non-human animal subject to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the regulatory element(s) [parameter 4];
the AAV capsid serotype(s) [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particle that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably treat macular degeneration.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of mammalian subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, rabbits, mice, and rats [056].
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).
Parameter 2
While Claims 5-6 recites a dosage of 1x10^8 to 1x10^10 vector genomes/eye, such merely speaks to the dosage of the rAAV to be administered to the subject, and not the anatomical route by which said rAAV dosage is to be administered to the subject.
Rather, the specification discloses the rAAV may be administered via parenteral, subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intracisternal, intradural, intracranial, intravenous, or other infusion routes [58].
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]).
It would be remedial for Applicant to amend Claims 5-6 to positively recite the step of administering to the subject’s eye a viral genome dosage of…, for example.
Parameter 3
The claimed methods are recited at a high level of generality for the rAAV 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 4
The claims are silent to the presence of a promoter operably linked to the sVEGFRv-1 cDNA. Thus, while it is clear that the rAAV genome comprises the cDNA, said cDNA is not expressed because of the absence of a promoter.
Rather, [46, 71] discloses that a promoter is operably linked to the sVEGFRv-1 cDNA, thereby promoting expression of said sVEGFRv-1 cDNA.
It would be remedial to amend the independent claim to positively recite the presence of a promoter operably linked to the sVEGFRv-1 cDNA.
Parameter 5
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 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?
For example:
[9] discloses “beneficial therapeutic effects”, which is an arbitrary and subjective determination.
[18] discloses choroidal neovascularization was inhibited and the size of the lesion was reduced.
[19] discloses “a therapeutic effect for several years”.
[29] discloses anti-angiogenic efficacy against neovascularization.
[30] discloses choroidal infiltration of inflammatory cells.
[31] discloses infiltration and fibrosis of inflammatory cells.
[32] discloses apoptosis (TUNEL-positive cells).
[50] discloses an inhibitory effect on retinal fibrosis.
[54] discloses anti-angiogenic, anti-inflammatory, and anti-fibrotic effects.
[128] discloses “reduction of apoptosis”.
If there are multiple phenotypic results by which “treating” is determined, 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 claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to reduce apoptosis, but does not achieve “a therapeutic effect for several years”, in a subject, e.g. rabbit, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that is necessarily and predictably able to achieve some arbitrary and subjective “beneficial therapeutic effects” yet is unable to reduce or inhibit choroidal neovascularization in a subject, e.g. monkey, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to achieve anti-angiogenic efficacy against neovascularization in a subject, e.g. guinea pig, but is unable to inhibit retinal fibrosis, nor inhibit choroidal infiltration of inflammatory cells, nor inhibit choroidal neovascularization in a subject, e.g. chicken, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intracisternally, that is necessarily and predictably able to achieve anti-angiogenic efficacy against neovascularization, but is unable to inhibit retinal fibrosis, nor inhibit choroidal infiltration of inflammatory cells, nor inhibit choroidal neovascularization in a subject, e.g. human, for example.
The instant claim as a whole does 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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Appropriate correction is required.
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).
4. Claim(s) 1 and 4-7 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 is directed to a method of treating macular degeneration comprising administering an effective amount of a recombinant AAV vector comprising a soluble VEGF receptor variant cDNA to a subject in need thereof.
The claim denotes 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).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the human or non-human animal subject to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the regulatory element(s) [parameter 4];
the AAV capsid serotype(s) [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particle that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” so as to necessarily and predictably treat macular degeneration.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of mammalian subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, rabbits, mice, and rats [056].
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).
Parameter 2
While Claims 5-6 recites a dosage of 1x10^8 to 1x10^10 vector genomes/eye, such merely speaks to the dosage of the rAAV to be administered to the subject, and not the anatomical route by which said rAAV dosage is to be administered to the subject.
Rather, the specification discloses the rAAV may be administered via parenteral, subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intracisternal, intradural, intracranial, intravenous, or other infusion routes [58].
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]).
It would be remedial for Applicant to amend Claims 5-6 to positively recite the step of administering to the subject’s eye a viral genome dosage of…, for example.
Parameter 3
The claimed methods are recited at a high level of generality for the rAAV 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 4
The claims are silent to the presence of a promoter operably linked to the sVEGFRv-1 cDNA. Thus, while it is clear that the rAAV genome comprises the cDNA, said cDNA is not expressed because of the absence of a promoter.
Rather, [46, 71] discloses that a promoter is operably linked to the sVEGFRv-1 cDNA, thereby promoting expression of said sVEGFRv-1 cDNA.
It would be remedial to amend the independent claim to positively recite the presence of a promoter operably linked to the sVEGFRv-1 cDNA.
Parameter 5
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 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?
For example:
[9] discloses “beneficial therapeutic effects”, which is an arbitrary and subjective determination.
[18] discloses choroidal neovascularization was inhibited and the size of the lesion was reduced.
[19] discloses “a therapeutic effect for several years”.
[29] discloses anti-angiogenic efficacy against neovascularization.
[30] discloses choroidal infiltration of inflammatory cells.
[31] discloses infiltration and fibrosis of inflammatory cells.
[32] discloses apoptosis (TUNEL-positive cells).
[50] discloses an inhibitory effect on retinal fibrosis.
[54] discloses anti-angiogenic, anti-inflammatory, and anti-fibrotic effects.
[128] discloses “reduction of apoptosis”.
If there are multiple phenotypic results by which “treating” is determined, 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 claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to reduce apoptosis, but does not achieve “a therapeutic effect for several years”, in a subject, e.g. rabbit, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that is necessarily and predictably able to achieve some arbitrary and subjective “beneficial therapeutic effects” yet is unable to reduce or inhibit choroidal neovascularization in a subject, e.g. monkey, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to achieve anti-angiogenic efficacy against neovascularization in a subject, e.g. guinea pig, but is unable to inhibit retinal fibrosis, nor inhibit choroidal infiltration of inflammatory cells, nor inhibit choroidal neovascularization in a subject, e.g. chicken, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. intracisternally, that is necessarily and predictably able to achieve anti-angiogenic efficacy against neovascularization, but is unable to inhibit retinal fibrosis, nor inhibit choroidal infiltration of inflammatory cells, nor inhibit choroidal neovascularization in a subject, e.g. human, for example.
"The claimed invention as a whole may not be adequately described if the claims require an essential or critical element which is not adequately described in the specification and which is not conventional in the art", "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus", "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''. MPEP §2163
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).
Possession may also be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was ''ready for patenting'' such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 1 19 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998), Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997)*, Amgen, Inc. v. Chugai Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by ''whatever characteristics sufficiently distinguish it'').
Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
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”).
Based on the applicant's specification, those of ordinary skill in the art cannot envision the detailed combination of the enormous genus of rAAV serotypes whose genomes encodes and expresses sVEGFRv-1, its corresponding dosage(s), and its corresponding administration route(s) to the enormous genus of animal subjects that is a “therapeutically effective amount” so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s) treating macular degeneration, as required by the independent claims.
At best, the specification discloses the use of AAV serotype 2, whereby said AAV2 vector encodes a CMV promoter operably linked to the sVEGFRv-1 cDNA (e.g. [84]), and is administered intravitreally to a rat subject at a dose of about (5x10^10 vg/mL; 0.005ml = 2.5x10^8 vector genomes/eye) [107].
While Examples 8-9 disclose administering a higher rAAV2-sVEGFRv-1 dosage/eye, the examples are obfuscatory by failing to disclose the anatomical route of administration.
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, the breadth of the claims reasonably encompasses:
an enormous genus of animal subjects to be treated by the method;
a very large genus of different rAAV serotypes having different cell-type specific tropisms;
an enormous genus of corresponding rAAV dosages;
an enormous genus of anatomically distinct administration routes, and
an enormous genus of phenotypically different results by which ‘treatment’ is to be determined,
that is a “therapeutically effective amount” so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), as required by the independent claims.
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”.
In the instant case, Applicant seeks to monopolize an entire class of treating macular degeneration without satisfying the real-world scientific and clinical nexus of the required rAAV vector dosages, let alone for rAAV vectors encoding, but not expressing sVEGFRv-1 (for lacking a promoter), to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), as required by the independent claims.
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
“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 make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
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.
5. Claims 1 and 4-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabling for a method of treating choroidal neovascularization in the eye of mammalian subject, the method comprising the step of administering to the mammalian subject’s eye by intravitreal injection a pharmaceutical composition comprising at least 1x10^8 to 1x10^10 AAV2 vector genomes/eye of an AAV2 virus whose genome comprises a CMV promoter operably linked to a cDNA encoding a soluble VEGFRv-1 consisting of the amino acid sequence of SEQ ID NO:1,
does not reasonably provide enablement for a nexus between an enormous genus of AAV vector serotypes, the enormous genus of rAAV vector dosages, and the enormous genus of anatomically distinct administration routes, so as to necessarily and predictably achieve a clinically meaningful, real-world therapeutic result treating macular degeneration.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
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 Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The nature of the invention involves one of the most complex and unpredictable areas of medicine molecular biology - gene therapy treatment.
The invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology." Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
Considering the mode of administration, the specification simply requires administration of the AAV to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols Daya et al (Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Ghoraba et al (Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses, Clinical Opthalmology 16: 1753-1771, 2022) is considered relevant post-filing art for having taught that the associated immune and inflammatory reactions to gene therapy, including rAAV-based gene therapies, may render such treatment ineffective or harmful, which are of particular concerns for the eyes due to their susceptibility to inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors (Abstract). Intravitreal administration, while convenient, is unable to transduce the outer retina layers, which is the main target of most retinal diseases due to defects in the RPE or photoreceptor cells (e.g. pg 1762, Intravitreal Delivery). Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response. The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies (pg 1763, para 1).
Acland et al (U.S. 2004/0022766) is considered relevant prior art for having disclosed a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid [0023], and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5' inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a coding sequence encoding a human Lebercilin [0031].
Acland et al disclosed [0057] “[T]he use of subretinal injection as the route of delivery is a critical component of this method, as intravitreal administration does not enable the same therapeutic effects. The vector and carrier cannot diffuse across the multiple cell layers in the retina to reach the RPE, when intravitreal injection is used. Similarly, intravenous delivery is unacceptable because the material does not penetrate the blood-brain (blood-retina) barrier. Because the virus does not diffuse well, topical administration is similarly not preferred for this method.”
Ye et al (Rescue of Cone ERG Function by Treatment with AAV-hCNGB3 Vectors in CNGB3 Knockout Mice, Invest. Ophthalmol. & Visual Sci. 56 (5477), ARVO Annual Meeting Abstract, June 2015; abstract only) is considered relevant prior art for having taught a method of treating achromatopsia (“Rescue of Cone ERG Function…in CNGB3 Knockout Mice”; “model of ACHM”), said method comprising the step of administering a pharmaceutical composition comprising an AAV encoding a codon-optimized CNGB3 operably linked to expression control sequences that direct expression of the CNGB3 in a host cell to the subject in need thereof, wherein the composition is administered subretinally, and wherein the AAAV vector dose administered is at least 5x10^9 vg/eye.
Wilson et al (Gene therapy for retinal ganglion cell neuroprotection in glaucoma, Gene Therapy 19: 127-136, 2012) is considered relevant prior art for having taught a gene therapy method for the treatment of glaucoma (Title), including human patients, the method comprising the administration of rAAV viral vectors to the eye via subretinal or intravitreal injection (pg 128, col. 1). In the case of neuroprotective gene therapy for adult-onset glaucoma, substantial hurdles still need to be overcome to translate successful preclinical findings to clinical applications. There might be patients who experience compromised retrograde axonal transport along the optic nerve and target-derived neurotrophin deprivation, whereas others might suffer from increased oxidative stress and reduced antioxidant defense mechanisms. Moreover, some individuals may suffer from alterations in multiple pathways that converge to trigger or exacerbate RGC death. Another important issue relates to the effect of long-term modification of gene expression, such as that provided by AAV, in glaucoma. For example, neurotrophic factor supplementation by gene therapy is a promising strategy to promote RGC survival in several models of optic nerve damage, but the long-term effect and safety of increased diffusible neurotrophin levels in the retina are currently unknown. (pg 134, col. 1). Intravitreal AAV injection of transduces a large number of retinal ganglion cells; whereas, subretinal AAV injection leads primarily to transduction of photoreceptors and retinal pigment epithelium (RPE) (pg 128, col. 1).
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.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
The gene therapy art is unpredictable, as manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells, routes of administration, the transient and unpredictable expression of the transgenes in target cells, the specific genes to be used for a treatment, the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method. The totality of the prior art appear to teach that at the time of filing while transient gene expression has been observed in cells in vivo using routes of administration other than local administration, it is not apparent how a subretinal injection achieving transient gene expression in an eye is reasonably correlated to a successful targeted gene therapy method employing administration via an enormous genus of anatomically distinct routes to an enormous genus of mammalian subjects at an enormous genus of unrecited AAV vector dosages to achieve a real-world, clinically meaningful therapeutic result, thereby treating achromatopsia, particularly given the doubts expressed in the art of record.
At best, the specification discloses the use of AAV serotype 2, whereby said AAV2 vector encodes a CMV promoter operably linked to the sVEGFRv-1 cDNA (e.g. [84]), and is administered intravitreally to a rat subject at a dose of about (5x10^10 vg/mL; 0.005ml = 2.5x10^8 vector genomes/eye) [107].
While Examples 8-9 disclose administering a higher rAAV2-sVEGFRv-1 dosage/eye, the examples are obfuscatory by failing to disclose the anatomical route of administration.
The specification fails to make up for deficiencies of the global scientific community, and thus the ordinary artisans must determine for themselves that which Applicant fails to disclose.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the broadly claimed genus of rAAV serotypes may be administered by the broadly encompassed administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result treating macular degeneration using sVEGFRv-1 gene therapy.
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to extrapolate the results provided in the instant specification of intravitreal administering the AAV2 vector encoding sVEGFRv-1 to the larger genus of AAV capsid serotypes having different cellular tropisms, the enormous genus of anatomically different administration routes, and the enormous genus of rAAV dosages reasonably encompassed by the claims. Neither the specification nor the claims provide the appropriate nucleic acid vector or viral dosage to be administered in the plurality of possible intravenous, intracranial, intraperitoneal, intramuscular, subcutaneous, intramuscular, intrarectal, intravaginal, intrathecal, intratracheal, intradermal, or transdermal injection, by oral or nasal administration means that would reasonably be expected by the ordinary artisan to necessarily and predictably achieve a clinically meaningful, real-world therapeutic result to treat retinal disease and photoreceptor loss present in achromatopsia.
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible AAV serotypes disclosed), routes of administration (as disclosed, do not even require direct administration to the eye tissue), the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), and the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
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”.
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).
Those of ordinary skill in the art would immediately recognize that the instant specification fails to establish the nexus between the broad genus of AAV vectors, the enormous genus of AAV vector dosages, and the corresponding enormous genus of anatomically distinct administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the enormous genus of human and non-human animal subjects encompassed by the claimed methods.
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.
The specification fails to make up for the deficiencies of the global scientific community.
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, the breadth of the claims reasonably encompasses:
an enormous genus of animal subjects to be treated by the method;
a very large genus of different rAAV serotypes having different cell-type specific tropisms;
an enormous genus of corresponding rAAV dosages;
an enormous genus of anatomically distinct administration routes, and
an enormous genus of phenotypically different results by which ‘treatment’ is to be determined,
that is a “therapeutically effective amount” so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), as required by the independent claims.
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”.
In the instant case, Applicant seeks to monopolize an entire class of treating macular degeneration without satisfying the real-world scientific and clinical nexus of the required rAAV vector dosages, let alone for rAAV vectors encoding, but not expressing sVEGFRv-1 (for lacking a promoter), to be administered to the enormous genus of human and non-human animals via the enormous genus of anatomically distinct routes so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s), as required by the independent claims.
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
“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 make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Accordingly, limiting the claims to a method of treating choroidal neovascularization in the eye of mammalian subject, the method comprising the step of administering to the mammalian subject’s eye by intravitreal injection a pharmaceutical composition comprising at least 1x10^8 to 1x10^10 AAV2 vector genomes/eye of an AAV2 virus whose genome comprises a CMV promoter operably linked to a cDNA encoding a soluble VEGFRv-1 consisting of the amino acid sequence of SEQ ID NO:1, is proper.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
6. Claims 1 and 4-6 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Constable et al (Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration, EBioMedicine 14: 168-175, 2016; of record in IDS) in view of Kendall et al (Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor, PNAS 90: 10705-10709, 1993; of record in parent application 16/858511 and IDS; hereafter Kendall-1), Markovic-Mueller et al (Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A, Structure 25: 341-352; available February 7, 2017; of record in parent application 16/858511), Rosendahl et al (U.S. 2009/0163411; of record in parent application 16/858511), and Kendall et al (U.S. 2007/0010442; hereafter Kendall-2).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
SEQ ID NO:1 encodes a sFlt1 variant of 656 amino acids, shown below.
MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIR*
Constable et al is considered relevant prior art for having taught a method of treating macular degeneration comprising the step of administering to the eye of a human subject in need thereof a recombinant vector expressing a soluble VEGF receptor variant cDNA (Title).
The sFlt-1 construct of Constable et al appears to be the naturally occurring sFlt-1 (see Kendall-1 (Figure 1), and thus is understood to have a C-terminal amino acid sequence shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIRGEHCNKKAVFSRISKFKSTRNDCTTQSNVKH*
Constable et al do not teach the sFlt-1 variant consists of 656 amino acids encoded by SEQ ID NO:1, which has a C-terminal amino acid sequence shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIR*
However, prior to the effective filing date of the instantly claimed invention, Markovic-Mueller et al is considered relevant prior art for having taught a recombinant expression vector, to wit, baculovirus expression vector (pg 342, col. 1; Supplementary Materials, Production and purification of recombinant proteins), encoding recombinant soluble VEGFR1 variants, including sFlt-1 (D1-6), residues 1-660.
Markovic-Mueller et al taught the D6 motif terminates at residue R654 (Figure 1a-b; pg 344, col. 1, “D6 (residues 555-654)”), which corresponds to residue R656, as shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIR*
The expression construct Markovic-Mueller et al comprises four additional, wildtype C-terminal amino acids, DQEA (see also Kendall et al, 1993, Figure 1a), as shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIRDQEA*
Similarly, Rosendahl et al is considered relevant prior art for having disclosed soluble VEGFR1 (syn. sFlt-1) variants to inhibit the activity of VEGF (Abstract), wherein said sFlt-1 variant comprises domains 1-6, and may further comprise the last three amino acids of the domain [0013], hence the sFlt-1 protein truncations consist essentially of domains 1-6, and may include the last one, two, or three amino acids of the domain [0043], as shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIR*
SLQDSGTYACRARNVYTGEEILQKKEITIRD*
SLQDSGTYACRARNVYTGEEILQKKEITIRDQ*
SLQDSGTYACRARNVYTGEEILQKKEITIRDQE*
Rosendahl et al disclosed the recombinant sFlt variants are encoded by expression vectors, e.g. plasmid ([0088], Example 2).
Rosendahl et al disclosed the sFlt-1 variants are useful for the treatment of conditions characterized or caused by abnormal or excessive angiogenesis, e.g. retinopathy and choroidal neovascularization [0075].
Neither Constable et al, Kendall-1, Markovic-Mueller et al, nor Rosendahl et al taught/disclosed the sFlt-1-encoding nucleic acid consists of the nucleotide sequence of instant SEQ ID NO:1.
However, prior to the effective filing date of the instantly claimed invention, Kendall-2 is considered relevant prior art for having disclosed a nucleic acid sequence encoding a soluble VEGFR (syn. sFlt1) protein (e.g. Figure 1; sVEGF-RI, sVEGF-RII), as shown below:
PNG
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88
596
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Greyscale
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media_image2.png
96
598
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Kendall et al disclosed a sFlt-1 embodiment (lower line) that is 663 amino acids in length, and thus would terminate with an amino acid sequence that is 7 amino acids longer than the instant sFlt-1 (upper line) encoded by SEQ ID NO:1, as shown below:
VYTGEEILQKKEITIR*
VYTGEEILQKKEITIRGEHCNKK*
Kendall-1 taught that Flt and sFlt share the same D6 motif terminating with KKEITIR (e.g. Figure 1), although the additional C-terminal amino acids may differ, e.g. DQEA…, as per Markovic-Mueller et al and Rosendahl et al, or GEHC…, as per Kendall-2.
Thus, it would have been obvious for one of ordinary skill in the art to terminate a sFlt-1 cDNA at the 3’ end with the nucleotide sequence --- AAGAAAGAAATTACAATCAGA (1972) of instant SEQ ID NO:1 because KKEITIR, encoded by said --- AAGAAAGAAATTACAATCAGA (1972), is the common, shared motif between Flt-1 and sFlt-1.
Kendall-2 disclosed a nucleic acid encoding a sFlt-1 polypeptide, e.g. SEQ ID NO: 17 (lower line), that has 100% identity to instant SEQ ID NO:1 (upper line, 1972 nucleotides), and comprises 5 additional nucleotides upstream of (5’ to) instant SEQ ID NO:1, as shown below:
CACCATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGC
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GCGCTCACCATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGC
-----
-----
-----
GAATGTATACACAGGGGAAGAAATCCTCCAGAAGAAAGAAATTACAATCAGA (1972)
||||||||||||||||||||||||||||||||||||||||||||||||||||
GAATGTATACACAGGGGAAGAAATCCTCCAGAAGAAAGAAATTACAATCAGA
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Nucleotides 1-4 of instant SEQ ID NO:1 are upstream of the ATG translation start codon (underlined).
There is no objective evidence that the presence of nucleotides 1-4 of SEQ ID NO:1 are material to patentability.
As demonstrated by Kendall-2, those of ordinary skill in the art previously recognized that they may truncate the sFlt-1-encoding cDNA to just a few nucleotides upstream of the ATG translation start codon to express sFlt-1 from the artisan’s expression vector.
There is no objective evidence that the presence of an additional 5 nucleotides (per Kendall et al) to nucleotides 1-4 of instant SEQ ID NO:1 is materially different and patentability distinct from instant SEQ ID NO:1 because both nucleic acids would encode a sFlt-1 protein.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology and the synthesis of recombinant proteins, including sFlt-1 variants. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first sFlt-1 variant, as taught by Constable et al, with a second sFlt-1 variant, i.e. a variant encoded by SEQ ID NO:1, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first sFlt-1 variant with a second sFlt-1 variant, i.e. a variant encoded by SEQ ID NO:1, because those of ordinary skill in the art previously recognized that the naturally occurring sFlt1 (D1-D6) comprise amino acids 1-656 of SEQ ID NO:1, with additional C-terminal, intron-encoded 31 amino acids (Kendall et al, Figure 1). Markovic-Mueller et al successfully demonstrated the ability to express recombinant sFlt1 (D1-D6) comprise amino acids 1-656 of SEQ ID NO:1, with four additional C-terminal amino acids, lacking the 31 intron-encoded amino acids of naturally-occurring sFlt1 (D1-D6), and taught that the D6 motif terminates at residue R656 (Figure 1a-b; pg 344, col. 1, “D6 (residues 555-654)”; syn. 557-656 of SEQ ID NO:1). Rosendahl et al disclosed sFlt variants consisting essentially of domains 1-6, and may include the last one, two, or three amino acids of the domain [0043]. Markovic-Mueller et al taught that recombinant soluble VEGFR1 D1-7 variants had significantly higher affinity to VEGF ligand than recombinant soluble VEGFR1 D1-3 variants. The presence of Ig domains 4-7 increased binding affinity for VEGF, presumably due to stabilization through homotypic receptor-receptor contacts in D4-7 (pg 346, col. 1).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to arrive at a sFlt-1-encoding nucleic acid consisting of SEQ ID NO:1 with a reasonable expectation of success and motivation because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) sFlt-2 variants comprise domains 1-6, and may further comprise the last three to four amino acids of the domain, hence the sFlt-1 protein truncations consist essentially of domains 1-6, and may include the last one, two, three, or four amino acids of the domain, as shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIRDQEA*;
SLQDSGTYACRARNVYTGEEILQKKEITIRDQE*;
SLQDSGTYACRARNVYTGEEILQKKEITIRDQ*;
SLQDSGTYACRARNVYTGEEILQKKEITIRD*; and
SLQDSGTYACRARNVYTGEEILQKKEITIR*;
ii) Flt and sFlt share the same D6 motif terminating with KKEITIR (e.g. Kendall-1, Figure 1), although the additional C-terminal amino acids may differ, e.g. DQEA…, as per Markovic-Mueller et al and Rosendahl et al, or GEHC…, as per Kendall-2, and thus, it would have been obvious for one of ordinary skill in the art to terminate a sFlt-1 cDNA at the 3’ end with the nucleotide sequence --- AAGAAAGAAATTACAATCAGA (1972) of instant SEQ ID NO:1 because KKEITIR, encoded by said --- AAGAAAGAAATTACAATCAGA (1972), is the common, shared motif between Flt-1 and sFlt-1 variants (Kendall-1, Markovic-Mueller et al, Rosendahl et al); and
iii) as demonstrated by Kendall-2, those of ordinary skill in the art previously recognized that they may truncate the sFlt-1-encoding cDNA to just a few nucleotides upstream of the ATG translation start codon to express sFlt-1 from the artisan’s expression vector.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Nucleotides 1-4 of instant SEQ ID NO:1 are upstream of the ATG translation start codon (underlined).
There is no objective evidence that the presence of nucleotides 1-4 of SEQ ID NO:1 are material to patentability.
There is no objective evidence that the presence of an additional 5 nucleotides (per Kendall et al) to nucleotides 1-4 of instant SEQ ID NO:1 is materially different and patentability distinct from instant SEQ ID NO:1 because both nucleic acids would encode a sFlt-1 protein.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The ordinary artisan previously recognized the ability to express sFlt1 (D1-D6) variants whose C-termini varied in length, as shown below:
SLQDSGTYACRARNVYTGEEILQKKEITIRGEHCNKKAVFSRISKFKSTRNDCTTQSNVKH
SLQDSGTYACRARNVYTGEEILQKKEITIRDQEA (Markovic-Mueller et al)
SLQDSGTYACRARNVYTGEEILQKKEITIRDQE (Rosendahl et al)
SLQDSGTYACRARNVYTGEEILQKKEITIRDQ (Rosendahl et al)
SLQDSGTYACRARNVYTGEEILQKKEITIRD (Rosendahl et al); and
SLQDSGTYACRARNVYTGEEILQKKEITIR (Markovic-Mueller et al; Rosendahl et al).
Instant specification fails to disclose an element of criticality for a sFlt1 (D1-D6) terminating at residue 656 (instant), as opposed to the sFlt1 (D1-D6) variants of Constable et al, Markovic-Mueller et al, Rosendahl et al, Kendall-1, and/or Kendall-2.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 4, Constable et al disclosed wherein the recombinant vector is adeno-associated virus (AAV) (Abstract, “rAAV.sFLT-1.AAV2 capsid”.
With respect to Claims 5-6, Constable et al disclosed wherein the rAAV.sFLT-1 is formulated at a concentration of about 1x10^10 vector genomes/100uL (low dose) or 1x10^11 vector genomes/100uL (high dose) (e.g. [0367]), and administering 40 to 100uL of the rAAV formulation per eye (e.g. [0393]; Example 11), which is equivalent to about 4x10^9, 1x10^10, 4x10^10, and 1x10^11 vector genomes/eye.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
7. Claims 1, 4, and 7 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Constable et al (2016; of record in IDS) in view of Kendall et al (1993; of record in parent application 16/858511; hereafter Kendall-1), Markovic-Mueller et al (available February 7, 2017; of record in parent application 16/858511), Rosendahl et al (U.S. 2009/0163411; of record in parent application 16/858511), and Kendall et al (U.S. 2007/0010442; hereafter Kendall-2).
as applied to Claims 1 and 4-6 above, and in further view of Rakoczy et al (Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial, Lancet 386: 2395-2403, 2015; co-authors to Constable et al above).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 7, Constable et al disclosed wherein the rAAV.sFLT-1 is administered subretinally (e.g. Abstract).
Constable et al do not disclose wherein the rAAV.sFLT-1 is administered intravitreally.
However, prior to the effective filing date of the instantly claimed invention, Rakoczy et al is considered relevant prior art for having taught that rAAV-sFLT-1 gene therapy treatment of ocular disorders, e.g. treatment of age-related macular degeneration, whereby the rAAV-sFLT-1 is administered subretinally (as per Constable et al) or intravitreally in clinical trials (e.g. pg 2396, col. 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute subretinal administration of an rAAV expressing sFlt-1 with intravitreal administration in a method of treating macular degeneration in a subject in need thereof with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute subretinal administration of an rAAV expressing sFlt-1 with intravitreal administration in a method of treating macular degeneration in a subject in need thereof because Rakoczy et al taught that rAAV-sFLT-1 gene therapy treatment of ocular disorders, e.g. treatment of age-related macular degeneration, comprises administration of the rAAV-sFLT-1 to the subject via either subretinal (as per Constable et al) or intravitreal routes in clinical trials (e.g. pg 2396, col. 1).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 4, Constable et al disclosed wherein the recombinant vector is adeno-associated virus (AAV) (Abstract, “rAAV.sFLT-1.AAV2 capsid”.
Rakoczy et al taught wherein the recombinant vector is adeno-associated virus (AAV) (e.g. pg 2396, col. 1, “rAAV2.sFLT01”.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
8. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638