Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed October 24, 2025.
Amendments
Applicant's response and amendments, filed October 24, 2025, is acknowledged.
Claims 1-12, 15, 21-22, 27, 29, 33-34, and 36 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative vector is a viral vector, as recited in Claim 2;
ii) the alternative virus is AAV, as recited in Claims 5-6;
iii) the alternative capsid is AAV2, as recited in Claims 10-11; and
iv) the alternative suicide gene, and its corresponding SEQ ID NO, is SEQ ID NO:1, as recited in Claims 12 and 15.
Claims 1-12, 15, 21-22, 27, 29, 33-34, and 36 are pending.
Claims 3-4, 9, and 21 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-2, 5-8, 10-12, 15, 22, 27, 29, 33-34, and 36 are under consideration.
Priority
This application is a continuation of PCT/US2020/061486 filed on November 20, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/938,879 filed on November 21, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on August 30, 2022 and October 24, 2025 that have been considered.
The information disclosure statement filed October 24, 2025 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.
Specification
1. The disclosure is objected to because of the following informalities:
pg 2, lines 24-27 disclose the suicide gene encodes an amino acid sequence of SEQ ID NO:1.
However, as evidenced by the sequence listing, SEQ ID NO:1 is a nucleic acid sequence, not amino acid sequence.
pg 3, lines 1-4 disclose the suicide gene encodes an amino acid sequence of SEQ ID NO:2.
However, as evidenced by the sequence listing, SEQ ID NO:2 is a nucleic acid sequence, not amino acid sequence.
pg 17, lines 35-39 disclose an FGF-18 polypeptide having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:3.
However, as evidenced by the sequence listing, SEQ ID NO:3 is a nucleic acid sequence, not amino acid sequence.
See, for example, pg 8, lines 8-9, “An exemplary wild-type human FGF-18 nucleic acid sequence is provided in… (SEQ ID NO: 3)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 recites wherein the viral vector comprises a capsid.
Claim 8, dependent upon Claim 7, recites wherein the capsid is either a naturally occurring capsid or an engineered capsid.
Claim 8 fails to further limit Claim 7 because it is natural law that there are only two capsid possibilities: either naturally occurring or engineered. Recitation of both options does not further limit Claim 7.
The specification fails to disclose a non-naturally occurring viral capsid that is also a non-engineered viral capsid, for example.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
3. Claims 15 and 22 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 15 recites wherein the suicide gene encodes an amino acid sequence at least 85% identity to the amino acid sequence of SEQ ID NO:1.
Claim 22 recites wherein the FGF-18 polypeptide encodes an amino acid sequence at least 85% identity to the amino acid sequence of SEQ ID NO:3.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
As a first matter, those of ordinary skill in the art have long-recognized that “encodes” refers to nucleic acid molecules, not polypeptides.
As a second matter, SEQ ID NO:1 is a nucleic acid sequence, not an amino acid sequence.
Similarly, SEQ ID NO:3 is a nucleic acid sequence, not an amino acid sequence.
Thus, “the amino acid sequence of SEQ ID NO:1” and “the amino acid sequence of SEQ ID NO:3” is/are not consistent with art-recognized lexicography.
See, instead, specification pg 8, lines 9-10, “an exemplary wild-type FGF-18 amino acid sequence is provided… (SEQ ID NO: 4)”.
See, also for example, pg 8, lines 8-9, “An exemplary wild-type human FGF-18 nucleic acid sequence is provided in… (SEQ ID NO: 3)”.
4. Claims 1-2, 5-8, 10-12, 15, 22, 27, 29, 33-34, and 36 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 recites a nucleic acid encoding an FGF-18 polypeptide, or a functional fragment thereof.
Claim 22 recites wherein the FGF-18 polypeptide has an amino acid sequence at least 85% identical to instant SEQ ID NO:3.
SEQ ID NO:4 is 207 amino acids.
85% identity allows for 31 amino acid insertions, deletions, and/or substitutions.
20^31 = 2x10^40 structurally and functionally undisclosed variants of FGF-18.
(www.calculator.net/exponent-calculator; last visited October 28, 2025)
The claimed genus of FGF-18 fragments reasonably encompasses an enormously vast genus of peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
Thus, the claims reasonably encompass as many as about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
Claim 15 recites a nucleic acid encoding SEQ ID NO:1 is 996 nucleotides in length, which would encode a polypeptide of 332 amino acids.
85% identity allows for 149 nucleotide insertions, deletions, and/or substitutions to the nucleotide sequence of SEQ ID NO:1.
4^149 = 5x10^89 structurally and functionally undisclosed variants of SEQ ID NO:1.
(www.calculator.net/exponent-calculator; last visited October 28, 2025)
A polypeptide of 332 amino acids having 85% identity to a reference amino acid sequence allows for 50 amino acid insertions, deletions, and/or substitutions.
20^50 = 1x10^65 structurally and functionally undisclosed variants of a suicide polypeptide of 332 amino acids having 85% identity to a reference amino acid sequence.
(www.calculator.net/exponent-calculator; last visited October 28, 2025)
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of structurally undisclosed 2x10^40 structurally and functionally undisclosed variants of FGF-18, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed FGF-18 peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
The claims fail to recite, and the specification fails to disclose, a first FGF-18 peptide fragment that is not “functional”, as opposed to a second FGF-18 peptide fragment that is necessarily and predictably “functional”.
The claims fail to recite, and the specification fails to disclose, how to transform or modify a first FGF-18 peptide fragment that is not “functional”, into a second FGF-18 peptide fragment that is necessarily and predictably “functional”.
The claims fail to recite, and the specification fails to disclose, a first FGF-18 polypeptide of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4 that is not “functional”, as opposed to a second FGF-18 polypeptide of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 that is necessarily and predictably “functional”.
The claims fail to recite, and the specification fails to disclose, how to transform or modify a first FGF-18 polypeptide of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 that is not “functional”, into a second FGF-18 polypeptide of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4 that is necessarily and predictably “functional”.
Rather, the instant specification only discloses the FGF-18 polypeptide having the amino acid sequence of SEQ ID NO:4.
The claims fail to recite, and the specification fails to disclose, a first suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 that does not have the functional property of encoding a suicide polypeptide, as opposed to a second suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 that necessarily and predictably has the functional property of encoding a suicide polypeptide, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or modify a first suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 that does not have the functional property of encoding a suicide polypeptide, into a second suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 that necessarily and predictably has the functional property of encoding a suicide polypeptide, for example.
Rather, the specification only discloses SEQ ID NO:1.
The claims fail to recite, and the specification fails to disclose, a first suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants that do not have the functional property of being a suicide polypeptide, as opposed to a second suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants that necessarily and predictably has the functional property of being a suicide polypeptide, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or modify a first suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants that do not have the functional property of being a suicide polypeptide, into a second suicide gene of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants that necessarily and predictably has the functional property of being a suicide polypeptide, for example.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial FGF-18 amino acid sequence of SEQ ID NO:4 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants so as to necessarily and predictably achieve the recited biological functional properties of being “functional”.
Similarly, knowing that the initial suicide gene nucleic acid sequence of SEQ ID NO:1 does not tell you anything at all about the structures (nucleic acid and amino acid sequences) of the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants that necessarily and predictably has the functional property of being a suicide polypeptide.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of FGF-18 polypeptide variants and functional fragments thereof encompasses an enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants.
Similarly, the claimed class of suicide genes encompasses an enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants.
“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 instant specification only discloses the FGF-18 polypeptide having the amino acid sequence of SEQ ID NO:4.
The instant specification only discloses the suicide polypeptide encoded by the nucleic acid sequence of SEQ ID NO:1.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of:
i) the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants; nor
ii) the enormously vast genus of about 5x10^89 structurally and functionally undisclosed variants of nucleic acid sequence of SEQ ID NO:1 encoding the enormously vast genus of about 1x10^65 structurally and functionally undisclosed polypeptide variants.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
See also the 55 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection below.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
5. Claim 33 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
As a first matter, Claim 33 recites the limitation "contacting a cell" (line 2) There is insufficient antecedent basis for this limitation in the claim because while it is clear the method is directed to “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell”, per the preamble, the claim does not recite that the cell to be contacted with the expression vector is said chondrocyte cell or said chondrocyte precursor cell. Thus, it is unclear which/what cell is to be contacted with the expression vector.
As a second matter, the claim is considered indefinite for failing to recite a positive process step that refers back to the preamble of the claim, being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted step is a correlation or recapitulation step at the end of the claim which restates the preamble. No step is recited that actually achieves the goal stated in the preamble. The claims do not have a step that clearly relates back to the preamble. It is unclear what additional, unrecited steps are a part of the claimed method and therefore the metes and bounds of the claimed subject matter are unclear. The positively recited action-taking step(s) of contacting an unknown cell with the expression vector, would appear to not be sufficient to achieve the requirement of the preamble “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell”. In order for the claimed method to be definite in terms of the metes and bounds of the invention, the claim must recite a method step that provides for the results of the method as claimed.
As a third matter, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. The phrase(s) “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell” is an intended use limitation, which does not contain any further structural limitations with respect to the claimed cell contacted with the expression vector (see MPEP §2114).
Either any cell contacted with the expression vector will inherently and naturally promote “proliferation in a chondrocyte cell or chondrocyte precursor cell”, per natural law of cell biology, or it will not, and something of the method must change.
To the extent the functional property “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell” is not an inherent property that naturally flows from the thus-contacted cell, then something must change. The claim is considered indefinite for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
The limitation “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell” merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the cell, recited at a high level of generality, contacted with the expression vector recited at a high level of generality, so it is unclear whether the claim requires some other structure(s) and/or method step(s) to provide the functional properties recited in the preamble.
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.
6. Claim 34 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
As a first matter, the claim is considered indefinite for failing to recite a positive process step that refers back to the preamble of the claim, being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted step is a correlation or recapitulation step at the end of the claim which restates the preamble. No step is recited that actually achieves the goal stated in the preamble. The claims do not have a step that clearly relates back to the preamble. It is unclear what additional, unrecited steps are a part of the claimed method and therefore the metes and bounds of the claimed subject matter are unclear. The positively recited action-taking step(s), contacting an unknown cell with the expression vector, would appear to not be sufficient to achieve the requirement of the preamble “promoting the secretion of extracellular matrix to replace cartilage”. In order for the claimed method to be definite in terms of the metes and bounds of the invention, the claim must recite a method step that provides for the results of the method as claimed.
As a second matter, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. The phrase(s) “promoting the secretion of extracellular matrix to replace cartilage” and/or “to replace cartilage” is/are an intended use limitation(s), which does not contain any further structural limitations with respect to the claimed cell contacted with the expression vector (see MPEP §2114).
Either any cell contacted with the expression vector will inherently and naturally “promote the secretion of extracellular matrix” and/or “to replace cartilage”, per natural law of cell biology, or it will not, and something of the method must change.
To the extent the functional property(ies) “promote the secretion of extracellular matrix” and/or “to replace cartilage” are not inherent properties that naturally flow from the thus-contacted cell, then something must change. The claim is considered indefinite for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
The limitation “promote the secretion of extracellular matrix” and/or “to replace cartilage” merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the cell, recited at a high level of generality, contacted with the expression vector recited at a high level of generality, so it is unclear whether the claim requires some other structure(s) and/or method step(s) to provide the functional properties recited in the preamble.
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.
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).
7. Claim(s) 33-34 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.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The claims reasonably encompass as many as about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
With respect to Claim 33, either any cell contacted with the expression vector will inherently and naturally promote “proliferation in a chondrocyte cell or chondrocyte precursor cell”, per natural law of cell biology, or it will not, and something of the method must change.
To the extent the functional property “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell” is not an inherent property that naturally flows from the thus-contacted cell, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
With respect to Claim 34, either any cell contacted with the expression vector will inherently and naturally “promote the secretion of extracellular matrix” and/or “to replace cartilage”, per natural law of cell biology, or it will not, and something of the method must change.
To the extent the functional property(ies) “promote the secretion of extracellular matrix” and/or “to replace cartilage” are not inherent properties that naturally flow from the thus-contacted cell, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
The limitations “promoting proliferation in a chondrocyte cell or chondrocyte precursor cell”, “promote the secretion of extracellular matrix” and/or “to replace cartilage”, merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the cell, recited at a high level of generality, contacted with the expression vector recited at a high level of generality, so it is unknown what other structure(s) and/or method step(s) is required to provide the functional properties recited in the preambles, respectively.
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)
8. Claims 29 and 33-34 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 29 is directed to methods of treating a cartilage disorder in a subject, the method comprising the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 33 is directed to methods of promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 34 is directed to methods of promoting the secretion of extracellular matrix to replace cartilage, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The claims reasonably encompass as many as about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the expression vector encoding about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length and suicide gene must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The claims also denote that there is an amount (syn. dosage) of the expression vector that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the structure(s) of the FGF-18 polypeptide and/or fragment thereof [parameter 2];
the structure of the therapeutic nucleic acid vector encoding said FGF-18 polypeptide and/or fragment thereof [parameter 3];
the administration route [parameter 4];
the dosage administered [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the expression vector, recited at a high level of generality, encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length and suicide gene that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of vertebrate subjects, including mammalian subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primates, cattle, pigs, horses, sheep, cats, dogs, mice, and rats (e.g. pg 25, line 40; pg 32, line 5; pg 10, lines 24-27).
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
As discussed in the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections, the claims suffer a gap in the nexus of the claimed cell(s) that is/are to be contacted with the expression vector and the results to be achieved per the recited preambles.
The art recognizes, for example, at least 1000 different types of cells just in the human body, e.g. erythrocytes, vascular endothelial cells, hepatocytes, neurons, glial cells, epidermal cells, fat cells, fibroblasts, myocytes, etc…. (List of distinct cell types in the adult human body, wikipedia.org/wiki/List_of_distinct_cell_types_in_the_adult_human_body; last visited June 13, 2024).
Parameter 2
As discussed in the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections, the claims reasonably encompass an enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length.
Parameter 3
The claimed methods are recited at a high level of generality for type of nucleic acid vectors encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length., said vectors including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles.
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 4
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Parameter 5
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claims also denote that there is an amount (syn. dosage) of the expression vector that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses “treating” encompasses:
i) slowing or lessening a undesired physiological condition, which itself is an arbitrary and subjective determination;
ii) obtain a beneficial or desired clinical result, which itself is an arbitrary and subjective determination;
iii) alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable;
iv) eliciting a clinically significant response without excessive levels of side effects, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination; and
v) preventative measures (e.g. pg 11, lines 14-24).
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing”.
(www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025)
If there are multiple ways to measure “therapeutically effective dose”, to wit, concentration, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34).
The claims fail to recite, and the specification fails to disclose, a first bacteriophage dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to promote the secretion of extracellular matrix to replace cartilage in a subject, as opposed to a second bacteriophage dosage administered via a second administration route, e.g. intravenously, that is unable to promote proliferation in a chondrocyte cell or a chondrocyte progenitor cell in a subject, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intrathecal injection, that is unable to diminish the extent of a cartilage disorder condition in a subject transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of diminishing the extent of a cartilage disorder condition in a subject, for example.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
9. Claim(s) 29 and 33-34 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 29 is directed to methods of treating a cartilage disorder in a subject, the method comprising the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 33 is directed to methods of promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 34 is directed to methods of promoting the secretion of extracellular matrix to replace cartilage, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the expression vector encoding about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length and suicide gene must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The claims also denote that there is an amount (syn. dosage) of the expression vector that upon administration to the subject is ineffective or unable to achieve the recited therapeutic effect(s).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the structure(s) of the FGF-18 polypeptide and/or fragment thereof [parameter 2];
the structure of the therapeutic nucleic acid vector encoding said FGF-18 polypeptide and/or fragment thereof [parameter 3];
the administration route [parameter 4];
the dosage administered [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the expression vector, recited at a high level of generality, encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length and suicide gene that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial FGF-18 amino acid sequence of SEQ ID NO:4 does not tell you anything at all about:
i) the structure (amino acid sequences) of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants so as to necessarily and predictably achieve the recited biological functional properties of being “functional” [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34), including, but not limited to, slowing or lessening a undesired physiological condition, which itself is an arbitrary and subjective determination, obtaining a beneficial or desired clinical result, which itself is an arbitrary and subjective determination, alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a clinically significant response without excessive levels of side effects, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination, and/or preventative measures [parameter 6].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed methods encompass:
i) an enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants so as to necessarily and predictably achieve the recited biological functional properties of being “functional” [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34), including, but not limited to, slowing or lessening a undesired physiological condition, which itself is an arbitrary and subjective determination, obtaining a beneficial or desired clinical result, which itself is an arbitrary and subjective determination, alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a clinically significant response without excessive levels of side effects, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination, and/or preventative measures [parameter 6].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34).
The instant specification only discloses the FGF-18 polypeptide having the amino acid sequence of SEQ ID NO:4.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the broadly claimed methods.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
See also the 55 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection below.
10. Claim(s) 29 and 33-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 29 is directed to methods of treating a cartilage disorder in a subject, the method comprising the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 33 is directed to methods of promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
Claim 34 is directed to methods of promoting the secretion of extracellular matrix to replace cartilage, the method comprising the step of contacting a cell with a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene. The breadth of the claims encompasses in vivo embodiments, e.g. the step of administering to the subject a composition comprising a nucleic acid expression vector encoding an FGF-18 polypeptide and suicide gene.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))).
The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial FGF-18 amino acid sequence of SEQ ID NO:4 does not tell you anything at all about:
i) the structure (amino acid sequences) of the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants so as to necessarily and predictably achieve the recited biological functional properties of being “functional” [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34), including, but not limited to, slowing or lessening a undesired physiological condition, which itself is an arbitrary and subjective determination, obtaining a beneficial or desired clinical result, which itself is an arbitrary and subjective determination, alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a clinically significant response without excessive levels of side effects, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination, and/or preventative measures [parameter 6].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed methods encompass:
i) an enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length variants so as to necessarily and predictably achieve the recited biological functional properties of being “functional” [parameter 2];
ii) the broad genus of vectors recited at a high level of generality, including, but not limited to plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses, dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [parameter 3];
iii) the multitude of anatomically distinct administration routes recited at a high level of generality, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic [parameter 4];
iv) the nucleic acid vector dosages recited at a high level of generality that is to be administered [parameter 5];
v) to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1];
vi) so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34), including, but not limited to, slowing or lessening a undesired physiological condition, which itself is an arbitrary and subjective determination, obtaining a beneficial or desired clinical result, which itself is an arbitrary and subjective determination, alleviation of symptoms, diminishment of the extent of a condition, stabilizing or not worsening a condition, delaying onset of a condition, slowing a condition, ameliorating a condition, whether detectable or undetectable, eliciting a clinically significant response without excessive levels of side effects, whereby “significant” and/or “excessive” are each themselves an arbitrary and subjective determination, and/or preventative measures [parameter 6].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The specification fails to disclose a reduction to practice of administering via the enormously broad genus of anatomically distinct administration routes [parameter 4] a therapeutically effective amount [parameter 5] of a nucleic acid vector recited at a high level of generality [parameter 3] encoding the enormously vast genus of about 2x10^40 structurally and functionally undisclosed variants of FGF-18 amino acid sequence of SEQ ID NO:4, as well as an enormously vast genus of structurally and functionally undisclosed peptides of just 2, 3, 4, 5, 10, 12, 15, 18, 20, etc…., amino acids in length [parameter 2] to the enormous genus of about 1000 anatomically and functionally distinct cell types of the about 1x10^6 species of animals [parameter 1] so as to necessarily and predictably achieve a real-world, clinically meaningful result of:
i) treating a cartilage disorder in a subject (Claim 29);
ii) promoting proliferation in a chondrocyte cell or a chondrocyte precursor cell in a subject (Claim 33); and/or
iii) promoting the secretion of extracellular matrix to replace cartilage in a subject (Claim 34).
The instant specification only discloses the FGF-18 polypeptide having the amino acid sequence of SEQ ID NO:4.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
11. Claim(s) 1-2, 5-8, 10-11, 22, and 33-34 are rejected under 35 U.S.C. 102(a)(1) and/or 102(a)(2) as being anticipated by Ostertag et al (U.S. 2019/0119658; of record).
With respect to Claim 1, Ostertag et al is considered relevant prior art for having disclosed a vector encoding FGF18 (e.g. [0241]; pg 83, Table 1), wherein said vector may further comprise a suicide gene (e.g. [0268]).
With respect to Claim 2, Ostertag et al disclosed wherein the vector is a viral vector (e.g. [0043]).
With respect to Claims 5-8, Ostertag et al disclosed wherein the viral vector is an AAV virus, which naturally comprises an AAV capsid protein (e.g. [0039]).
With respect to Claims 10-11, Ostertag et al disclosed wherein the AAV capsid is AAV2 (e.g. [0039]).
With respect to Claim 22, Ostertag et al disclosed wherein the FGF-18 nucleic acid is ENSG00000156427 (e.g. pg 83, Table 1), whereby said FGF-18 nucleic acid naturally encodes an amino acid sequence that is at least 100% identical to instant SEQ ID NO:4, as shown below:
MYSAPSACTCLCLHFLLLCFQVQVLVAEENVDFRIHVENQTRARDDVSRKQLRLYQLYSR
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MYSAPSACTCLCLHFLLLCFQVQVLVAEENVDFRIHVENQTRARDDVSRKQLRLYQLYSR
TSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKP
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKP
DGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPK
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPK
GQPELQKPFKYTTVTKRSRRIRPTHPA
|||||||||||||||||||||||||||
GQPELQKPFKYTTVTKRSRRIRPTHPA
With respect to Claims 33-34, Ostertag et al disclosed wherein a host cell is contacted with the expression vector (e.g. [0262, 274]).
Ostertag et al disclosed the positively recited method steps, and thus fulfills the instant claims. To the extent Applicant argues otherwise, then see the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections above.
Thus, Ostertag et al anticipate the 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.
12. Claims 2, 5-8, 27, and 36 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ostertag et al (U.S. 2019/0119658; of record), as applied to Claims 1-2, 5-8, 10-11, 22, and 33-34 above, and in further view of Green et al (Two Animal Models of Retinal Degeneration Are Rescued by Recombinant Adeno-associated Virus-Mediated Production of FGF-5 and FGF-18, Molecular Therapy 3(4): 507-515, 2001).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Ostertag et al do not disclose a pharmaceutical composition comprising the expression vector encoding FGF-18.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 27, Green et al is considered relevant prior art for having taught a pharmaceutical composition comprising an AAV expression vector encoding FGF-18 (e.g. pg 508, col. 2, Methods, rAAV production).
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 gene expression vectors. 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 arrive at a pharmaceutical composition comprising an expression vector of Ostertag et al encoding FGF-18 with a reasonable expectation of success because those of ordinary skill in the art have long-practiced the routine step of purifying the artisan’s expression vector of interest, including an expression vector encoding FGF-18 (Green et al), and diluting it in a pharmaceutically acceptable carrier such as isotonic buffer solution, as successfully demonstrated by Green et al.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 2, Ostertag et al disclosed wherein the vector is a viral vector (e.g. [0043]).
Green et al taught wherein the viral vector is an AAV virus (e.g. pg 508, col. 2, Methods, rAAV production).
With respect to Claims 5-8, Ostertag et al disclosed wherein the viral vector is an AAV virus, which naturally comprises an AAV capsid protein (e.g. [0039]).
Green et al taught wherein the viral vector is an AAV virus, which naturally comprises an AAV capsid protein (e.g. pg 508, col. 2, Methods, rAAV production; see also citations 21-23).
With respect to Claims 33-34, Ostertag et al disclosed wherein a host cell is contacted with the expression vector (e.g. [0262, 274]).
Green et al taught wherein a host cell is contacted with the rAAV-FGF-18 expression vector (e.g. pg 508, col. 2, Methods, Injections; Figures 2-3).
Ostertag et al and Green et al taught/disclosed the positively recited method steps, and thus fulfills the instant claims. To the extent Applicant argues otherwise, then see the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections above.
With respect to Claim 36, Green et al taught a kit comprising the rAAV-FGF-18 vector, e.g. purified rAAV (e.g. pg 508, col. 2, Methods, rAAV production).
Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed, explaining "[i]f we were to adopt [applicant’s] position, anyone could continue patenting a product indefinitely provided that they add a new instruction sheet to the product."). See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983) ( "Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability….[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate." ); In re Miller, 418 F.2d 1392, 1396 (CCPA 1969) (finding a new and nonobvious relationship between a measuring cup and writing showing how to "half" a recipe). See MPEP 2112.01(III).
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.
13. Claim(s) 22 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Ostertag et al (U.S. 2019/0119658; of record), as applied to Claims 1-2, 5-8, 10-11, 22, and 33-34 above, and in further view of de Fougerolles et al (U.S. 2014/0343129).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Ostertag et al disclosed wherein the FGF-18 nucleic acid is ENSG00000156427 (e.g. pg 83, Table 1), whereby said FGF-18 nucleic acid naturally encodes an amino acid sequence that is at least 100% identical to instant SEQ ID NO:4, as shown below:
MYSAPSACTCLCLHFLLLCFQVQVLVAEENVDFRIHVENQTRARDDVSRKQLRLYQLYSR
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MYSAPSACTCLCLHFLLLCFQVQVLVAEENVDFRIHVENQTRARDDVSRKQLRLYQLYSR
TSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKP
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKP
DGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPK
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPK
GQPELQKPFKYTTVTKRSRRIRPTHPA
|||||||||||||||||||||||||||
GQPELQKPFKYTTVTKRSRRIRPTHPA
Ostertag et al do not disclose wherein the FGF-18 encoding nucleic acid is at least 85% identical to the nucleic acid sequence of instant SEQ ID NO:3.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 22, de Fougerolles et al is considered relevant prior art for having disclosed an FGF-18 encoding nucleic acid sequence (e.g. SEQ ID NO:80) that is 100% identical to nucleotides 10-1995 of instant SEQ ID NO:3.
Nucleotides 1-9 of SEQ ID NO:3 are 5’ upstream of the ATG start codon, and thus it is axiomatic that the nucleotide sequence of de Fougerolles et al’s SEQ ID NO:80 inherently and naturally encodes an FGF-18 amino acid sequence that is 100% identical to the amino acid sequence of instant SEQ ID NO:4.
de Fougerolles et al do not disclose nucleotides 1-9 of instant SEQ ID NO:4.
GGGAGGCGG
However, these are 5’ non-coding nucleotides and there is no objective evidence in the instant application that these are an inventive concept, let alone substantive of and/or dispositive for the instantly recited FGF-18 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.
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 FGF-18 encoding nucleic acid sequence with a second FGF-18 encoding nucleic acid sequence that is 100% identical to nucleotides 10-1995 of instant SEQ ID NO:3, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first FGF-18 encoding nucleic acid sequence with a second FGF-18 encoding nucleic acid sequence that is 100% identical to nucleotides 10-1995 of instant SEQ ID NO:3 because those of ordinary skill in the art had previously reduced to practice expressing FGF-18 from a nucleic acid sequence that is 100% identical to nucleotides 10-1995 of instant SEQ ID NO:3.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
14. Claim(s) 2, 5-8, 12, 27, 33-34, and 36 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ostertag et al (U.S. 2019/0119658; of record), as applied to Claims 1-2, 5-8, 10-11, 22, and 33-34 above, and in further view of Rosenblum et al (U.S. 2003/0176331).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Ostertag et a disclosed a vector encoding FGF18 (e.g. [0241]; pg 83, Table 1), wherein said vector may further comprise a suicide gene (e.g. [0268]).
Ostertag et al do not disclose wherein the suicide gene encodes HSV thymidine kinase.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 12, Rosenblum et al is considered relevant prior art for having disclosed nucleic acid expression vectors (e.g. [0034, 62, 155-157]) encoding FGF-18 (e.g. Table 2), wherein said vectors may further comprise an HSV thymidine kinase suicide gene (e.g. [0196]).
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 suicide gene with a second suicide gene, to wit, HSV thymidine kinase, in an FGF-18 expression vector with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first suicide gene with a second suicide gene, to wit, HSV thymidine kinase, in an FGF-18 expression vector because Rosenblum et al disclosed expression vectors encoding FGF-18, wherein said expression vectors may further comprise a nucleic acid encoding HSV thymidine kinase, as HSV tk was an art-recognized enzyme with which to select for target cells comprising the artisan’s expression vector of interest [0196].
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 2, Ostertag et al disclosed wherein the vector is a viral vector (e.g. [0043]).
Rosenblum et al disclosed wherein the expression vectors include viral vectors (e.g. [0169-170; 0206]), including AAV vectors (e.g. [0034, 208]).
With respect to Claims 5-8, Ostertag et al disclosed wherein the viral vector is an AAV virus, which naturally comprises an AAV capsid protein (e.g. [0039]).
Rosenblum et al disclosed wherein the expression vectors include AAV vectors (e.g. [0034, 208]), which naturally comprises an AAV capsid protein.
With respect to Claims 33-34, Ostertag et al disclosed wherein a host cell is contacted with the expression vector (e.g. [0262, 274]).
Rosenblum et al disclosed wherein a host cell is contacted with the expression vector (e.g. [0170, 207, 245]).
Ostertag et al and Rosenblum et al disclosed the positively recited method steps, and thus fulfills the instant claims. To the extent Applicant argues otherwise, then see the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections above.
With respect to Claim 27, Rosenblum et al disclosed pharmaceutical compositions comprising the expression vector (e.g. [0352-353]).
With respect to Claim 36, Rosenblum et al disclosed a kit comprising pharmaceutical compositions comprising the expression vector (e.g. [0352-353]).
Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed, explaining "[i]f we were to adopt [applicant’s] position, anyone could continue patenting a product indefinitely provided that they add a new instruction sheet to the product."). See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983) ( "Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability….[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate." ); In re Miller, 418 F.2d 1392, 1396 (CCPA 1969) (finding a new and nonobvious relationship between a measuring cup and writing showing how to "half" a recipe). See MPEP 2112.01(III).
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
15. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638