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 February 8, 2024.
Amendments
Applicant's amendments, filed February 8, 2024, is acknowledged. Applicant has cancelled Claims 1-42, and entered new claims, Claims 43-62.
Claims 43-62 are pending and under consideration.
Priority
This application is a continuation of application 16/573,321 filed September 17, 2019, now U.S. Patent 11,858,969. Applicant’s claim for the benefit of a prior-filed application provisional application 62/732,953 filed on September 18, 2018 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 an Information Disclosure Statement on December 1, 2023 that has been considered.
The information disclosure statement filed December 1, 2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claims 60-62 are objected to because of the following informalities: the claims recite “administrating”, which is a different verb than ‘administering’ (Claim 43).
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 51 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 51 recites the broad recitation “electrically active cell” (whatever that might be), and the claim also recites “retinal cells” and “neuronal cells”, which is/are the narrower statement(s) of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
3. Claim 51 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.
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). Claim 51 recites the terms “monocular neuronal cells” and “binocular neuronal cells”. The terms are indefinite because neither the claims nor the specification actually provide a definition of these terms.
What type of neuronal cell is “monocular”, as opposed to “binocular”?
Appropriate correction is required.
4. Claim 56 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 56 recites the broad recitation “wherein administering to the subject comprises”, and the claim also recites “into the lateral geniculate nucleus of the subject”, which is/are the narrower statement(s) of the range/limitation.
The term "comprises" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Independent Claim 43 is generic to the route of administration to be performed.
Claim 56 is also generic to the route of administration to be performed. Mere recitation of “into the lateral geniculate nucleus of the subject” fails to further limit the genus of routes of administration to be performed, as such is not excluded from the genus of Claim 43, nor does it appear to be a required limitation of Claim 56.
The Examiner suggests amending Claim 56 to instead recite “administering to the subject is into the lateral geniculate nucleus of the subject”. See, for example, Claim 55, “administering is”.
Appropriate correction is required.
5. Claims 61-62 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 43 recites a method of ameliorating blindness or vision loss of a subject suffering from blindness or vision loss, the method comprising the step of administering to said subject:
a protein;
a nucleic acid encoding the protein; or
an isolated cell comprising the protein or the nucleic acid encoding the protein,
wherein the protein comprises an amino acid sequence having at least 95% sequence
identity to SEQ ID NOs: 5-19, 21-42, 44, 46-49, 51-56, 58, 60-71, 73-74, 76-139, 141-147, 149-
154, 157-175, and 178-196,
thereby improving or restoring light sensitivity of the subject.
Claim 61 recites wherein the method fully or partially restores or enhances vision of the subject.
Claim 62 recites wherein the method restores or enhances the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject.
Either the functional/phenotypic properties of Claims 61-62 are inherent properties of (that naturally flow from) the method of independent Claim 43 that achieves “improving or restoring light sensitivity of the subject”, or they are not, and something of independent Claim 43 method must change.
To the extent they are inherent properties of (that naturally flow from) the method of the independent claim, then the instant claims fail to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the "wherein” clauses of Claims 61-62 do not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the results of method positively recited in the independent claim. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The claims fail to recite, and the specification fails to disclose, a method that improves or restores light sensitivity of the subject (Claim 43) that does not also fully or partially restores or enhances vision of the subject (Claim 61) and/or restores or enhances the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
'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).
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.
To the extent Applicant argues otherwise, see 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and/or 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) below.
6. Claims 61-62 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 43 recites a method of ameliorating blindness or vision loss of a subject suffering from blindness or vision loss, the method comprising the step of administering to said subject:
a protein;
a nucleic acid encoding the protein; or
an isolated cell comprising the protein or the nucleic acid encoding the protein,
wherein the protein comprises an amino acid sequence having at least 95% sequence
identity to SEQ ID NOs: 5-19, 21-42, 44, 46-49, 51-56, 58, 60-71, 73-74, 76-139, 141-147, 149-
154, 157-175, and 178-196,
thereby improving or restoring light sensitivity of the subject.
Claim 61 recites wherein the method fully or partially restores or enhances vision of the subject.
Claim 62 recites wherein the method restores or enhances the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject.
Either the functional/phenotypic properties of Claims 61-62 are inherent properties of (that naturally flow from) the method of independent Claim 43 that achieves “improving or restoring light sensitivity of the subject”, or they are not, and something of independent Claim 43 method must change.
To the extent they are not inherent properties of (that naturally flow from) the method of the independent claim, then something must change. The claims are considered indefinite for failing to recite the change in the Claim 43 method that is/are necessary and sufficient to cause the recited functional language.
Furthermore, in regard to instant claims, it is noted that the "wherein” clauses of Claims 61-62 do not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the results of method positively recited in the independent claim. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The claims fail to recite, and the specification fails to disclose, a method that improves or restores light sensitivity of the subject (Claim 43) that does not also fully or partially restores or enhances vision of the subject (Claim 61) and/or restores or enhances the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
'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 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.
7. Claims 43-62 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 43 recites a method of ameliorating blindness or vision loss of a subject suffering from blindness or vision loss, the method comprising the step of administering to said subject:
i) a protein;
ii) a nucleic acid encoding the protein; or
iii) an isolated cell comprising the protein or the nucleic acid encoding the protein,
wherein the protein comprises an amino acid sequence having at least 95% sequence
identity to SEQ ID NOs: 5-19, 21-42, 44, 46-49, 51-56, 58, 60-71, 73-74, 76-139, 141-147, 149-
154, 157-175, and 178-196,
thereby improving or restoring light sensitivity of the subject.
Vas-cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.'' (See page 1117.) The specification should “clearly allow persons of ordinary skill in the art to recognize that (he or she) invented what is claimed.'' (See Vas-cath at page 1116).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
It is understood that in order to meaningfully ameliorate blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62), 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, even if not recited ipsis verbis, of the protein, nucleic acid molecule, and/or cell expressing the enormous genus of light-sensitive proteins must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of human or non-human animal subject to be treated [parameter 1];
the type of target cell to which the pharmaceutical is administered [parameter 2];
the structure/function of the protein [parameter 3];
the pharmaceutical formulation itself, to wit, a protein, a nucleic acid encoding said protein, and/or a cell expressing said protein [parameter 4];
the dosage administered of said protein, nucleic acid encoding said protein, and/or cell expressing said protein [parameter 5]; and
the administration route [parameter 6].
The claims denote that there is an amount (syn. dosage) of the protein, nucleic acid encoding the protein, and/or cell expressing said protein that upon administration to the subject in need is ineffective or unable to achieve the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
That is to say, the claims denote that there is an amount of the pharmaceutical composition that upon administration to the subject is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are enormously broad for encompassing essentially any mammalian subject “in need”. [0016, 47, 68] discloses the subject can be, but is not limited to, e.g. domestic, farm, zoo, sports, or pet animals, including mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, monkeys, chimpanzees, apes, and humans.
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; of record in parent application 16/573,321), including insects, avians, reptiles, and mammals, 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; of record in parent application 16/573,321).
Parameter 2
The claims are broad in that the target cell(s) (Claim 43) to which the therapeutic is administered in recited at a high level of generality, including, but not limited to:
i) non-retinal cells (contrast with Claims 51-52);
ii) non-neuronal cells (contrast with Claims 51 and 53);
iii) non-(monocular) neuronal cells (contrast with Claim 51);
iv) non-(binocular) neuronal cells (contrast with Claim 51);
v) non-electrically active cells (contrast with Claims 51 and 54);
vi) non-rod cells (contrast with Claim 52); and/or
vii) non-cone cells (contrast with Claim 52).
The art recognizes that there are at least 1000 different cell types in the human body, e.g. erythrocytes, endothelial cells, monocytes, hepatocytes, dermal fibroblasts, muscle cells, etc… (List of distinct cell types in the adult human body; Wikipedia; en.wikipedia.org/wiki/list; last visited June 13, 2024).
Parameter 3
Claim 43 recites the protein comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NOs: 5-19, 21-42, 44, 46-49, 51-56, 58, 60-71, 73-74, 76-139, 141-147, 149-154, 157-175, and 178-196, which range from about 315 to 360 amino acids in length.
The breadth of the claims encompasses about 18 amino acid insertions, deletions, and/or substitutions, which is about 2x10^23 variants (20^18) of each referenced SEQ ID NO, respectively (calculator.net/exponent-calculator.html; last visited June 25, 2026).
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 and functionally undisclosed SEQ ID NO variants to necessarily and predictably have the recited functional property(ies) of achieving a real-world, clinically meaningful amelioration of blindness or vision loss in a subject by improving or restoring light sensitivity in said subject.
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%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally and functionally disclosed, enormously vast genus of 2x10^23 variants for each SEQ ID NO, respectively, 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.
Therefore, based on the discussions above concerning the specific examples of structurally similar proteins that have different functions, along with the art's recognition that one cannot rely upon structural similarity alone to determine functionality, the specification fails to reasonably inform the ordinary artisan how to make and use the claimed enormously vast genus of structurally undisclosed enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that necessarily and predictably have the disclosed and recited biological and functional properties.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention.
Parameter 4
The claims are broad for reciting a multitude of structurally different pharmaceutical formulations, whereby the pharmaceutical formulation comprises a protein, a nucleic acid encoding said protein, or a cell expressing said protein.
The breadth of the claimed nucleic acid vectors, including, but not limited to, plasmids, viral vectors, naked DNA, liposomes, cosmids, bacterial chromosomes [0037], bacteriophages, and transposons.
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).
The claims are enormously broad for reciting a multitude of anatomically and physiologically distinct genetically modified host cells expressing the protein(s) that are to be administered to the subject, including, but not limited to, bacterial cells, yeast cells, insect cells, plant cells, or combinations thereof [0068].
The claims are enormously broad for encompassing about 0.8 to 1.6 million species of prokaryotes (Louca et al, A census-based estimate of Earth’s bacterial and archaeal diversity, PLoS Biology 17(2): e3000106, 30 pages, doi.org/10.1371/journal.pbio.3000106, available online February 4, 2019).
Mongabay (How many plant species are there in the world? Scientists now have an answer, news.mongabay.com/2016/05/many-plants-world-scientists-may-now-answer/; May 12, 2016; last visited January 7, 2020; of record in parent application 16/573,321) is considered relevant prior art for having taught that there is an estimated 391,000 different vascular plant species currently known to science, according to a report by the Royal Botanic Gardens, Kew, in the United Kingdom.
The claims are enormously broad for reasonably encompassing about 30 million insect species (Smithsonian, Numbers of Insects (Species and Individuals), si.edu/spotlight/buginfo/bugnos; 1996).
Parameter 5
The claims are enormously broad for failing to recite the dosage of said:
i) protein;
ii) nucleic acid encoding said protein; and/or
iii) cell expressing said protein,
that is/are to be administered to the subject, thereby necessarily and predictably achieving the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
The claims denote that there is an amount (syn. dosage) of the:
i) protein;
ii) nucleic acid encoding said protein; and/or
iii) cell expressing said protein,
that upon administration to the subject in need is ineffective or unable (syn. subtherapeutic) to achieve the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
That is to say, the claims denote that there is an amount of the pharmaceutical composition that upon administration to the subject is not, in fact, “a therapeutically effective amount”.
The specification is silent to the dosage(s) of said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject.
The specification fails to disclose a working example of administering a protein pharmaceutical.
The specification is silent to the dosage(s) of said enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject.
The specification fails to disclose a working example of administering a cell pharmaceutical.
The specification is silent to the dosage(s) of said enormous genus of nucleic acid vectors encoding the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject.
While Example 7 discloses intravenous administration of a rAAV-PHP.eB virus to a mouse subject, such fails to disclose the dosage of said rAAV-PHP.eB virus.
Rather, the claimed methods are recited at a high level of generality, whereby the rAAV vector dosage to be administered, includes, but is 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]).
Example 7 fails to disclose that intravenous administration achieved “ameliorating blindness or vision loss” of the subject. Rather, all that the Example demonstrates is that the transgenic protein is expressed in the transduced cell, and that the recombinant protein is activated upon a specific photocurrent wavelength.
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of anatomically distinct routes by which the protein, nucleic acid encoding said protein, and/or cell expressing said protein are to be administered to the subject. The specification discloses administration routes such as intravitreal, intravenous, intraocular, subretinal, stereotactic injection, and cannula implantation [0088, 117].
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]).
Absent objective evidence to the contrary, it would be remedial for Applicant to amend independent Claim 43 to positively recite the step of administering to the subject’s eye…, for example.
Considering the mode of administration, the specification simply requires administration of the protein, nucleic acid encoding said protein, and/or said genetically modified host cell expressing said protein to the enormous genus of animal subjects by an enormous genus of anatomically distinct routes. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013; of record in parent application 16/573,321) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols Daya et al (Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶; of record in parent application 16/573,321). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Ghoraba et al (Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses, Clinical Opthalmology 16: 1753-1771, 2022) is considered relevant post-filing art for having taught that the associated immune and inflammatory reactions to gene therapy, including rAAV-based gene therapies, may render such treatment ineffective or harmful, which are of particular concerns for the eyes due to their susceptibility to inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors (Abstract). Intravitreal administration, while convenient, is unable to transduce the outer retina layers, which is the main target of most retinal diseases due to defects in the RPE or photoreceptor cells (e.g. pg 1762, Intravitreal Delivery). Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response. The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies (pg 1763, para 1).
Acland et al (U.S. 2004/0022766) is considered relevant prior art for having disclosed a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid [0023], and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5' inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a coding sequence encoding a human Lebercilin [0031].
Acland et al disclosed [0057] “[T]he use of subretinal injection as the route of delivery is a critical component of this method, as intravitreal administration does not enable the same therapeutic effects. The vector and carrier cannot diffuse across the multiple cell layers in the retina to reach the RPE, when intravitreal injection is used. Similarly, intravenous delivery is unacceptable because the material does not penetrate the blood-brain (blood-retina) barrier. Because the virus does not diffuse well, topical administration is similarly not preferred for this method.”
Wilson et al (Gene therapy for retinal ganglion cell neuroprotection in Glaucoma, Gene Therapy 19: 127-136, 2012) is considered relevant prior art for having taught a gene therapy method for the treatment of glaucoma (Title), including human patients, the method comprising the administration of rAAV viral vectors to the eye via subretinal or intravitreal injection (pg 128, col. 1). In the case of neuroprotective gene therapy for adult-onset glaucoma, substantial hurdles still need to be overcome to translate successful preclinical findings to clinical applications. There might be patients who experience compromised retrograde axonal transport along the optic nerve and target-derived neurotrophin deprivation, whereas others might suffer from increased oxidative stress and reduced antioxidant defense mechanisms. Moreover, some individuals may suffer from alterations in multiple pathways that converge to trigger or exacerbate RGC death. Another important issue relates to the effect of long-term modification of gene expression, such as that provided by AAV, in glaucoma. For example, neurotrophic factor supplementation by gene therapy is a promising strategy to promote RGC survival in several models of optic nerve damage, but the long-term effect and safety of increased diffusible neurotrophin levels in the retina are currently unknown. (pg 134, col. 1). Intravitreal AAV injection of transduces a large number of retinal ganglion cells; whereas, subretinal AAV injection leads primarily to transduction of photoreceptors and retinal pigment epithelium (RPE) (pg 128, col. 1).
Dalkara et al (Let There Be Light: Gene and Cell Therapy for Blindness, Human Gene Therapy 27(2): 134-147, 2016) is considered relevant prior art for having taught that cell therapy represents an alternative to gene therapy to restore retinal degenerative conditions (e.g. pg 140, col. 2). While animal models have indicated encouraging morphological and functional results, such were achieved using RPE cells or retinal progenitor cells, e.g. pluripotent stem cells or other stem cells. However, integration into the host retina and reconstruction of functional neural circuitry remains a major hurdle for successful cell transplantation (e.g. pg 141, col. 1). Although stem cell therapy carries great potential for the treatment of retinal degeneration, its
advancement to clinical translation faces multiple challenges. Among the most important are health and ethical issues associated with the nature of most stem cell types, such as risks of tumorigenesis associated with reprogramming and immunogenic responses. The type and number of cells needed for effective treatment, transplanted cell survival, and the functional outcomes remain questions of major importance for successful stem cell-based therapies in the clinic. Finally, production and delivery of clinical-grade stem cells involve unique regulatory and quality control requirements that need to be clearly established (pg 144, col. 1).
The prior art does not teach the use of bacterial, protozoal, fungal, plant, or insect cells in cell transplantation therapies for the treatment of blindness or vision loss.
The prior art does not teach the use of red blood cells, monocytes, lymphocytes, endothelial cells, myocytes, fibroblasts, hepatocytes, epithelial cells, etc… in cell transplantation therapies for the treatment of blindness or vision loss.
The claims fail to recite, and the specification fails to disclose, the real-world nexus between the enormous genus of proteins dosage(s) to be administered, and the corresponding administration route(s) that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
The claims fail to recite, and the specification fails to disclose, the real-world nexus between the enormous genus of nucleic acid dosage(s) to be administered, and the corresponding administration route(s) that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
The claims fail to recite, and the specification fails to disclose, the real-world nexus between the enormous genus of genetically modified host cell dosage(s) to be administered, and the corresponding administration route(s) that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
Claim 61 recites wherein the method fully or partially restores or enhances vision of the subject.
Claim 62 recites wherein the method restores or enhances the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject.
Either the functional/phenotypic properties of Claims 61-62 are inherent properties of (that naturally flow from) the method of independent Claim 43 that achieves “improving or restoring light sensitivity of the subject”, or they are not, and something of independent Claim 43 method must change.
To the extent they are not inherent properties of (that naturally flow from) the method of the independent claim, then something must change. The claims are considered to lack adequate written description for failing to recite the change in the Claim 43 method that is/are necessary and sufficient to cause the recited functional language.
"The claimed invention as a whole may not be adequately described if the claims require an essential or critical element which is not adequately described in the specification and which is not conventional in the art", "when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus", "in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus''. MPEP §2163
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).
Possession may also be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was ''ready for patenting'' such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 1 19 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998), Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997)*, Amgen, Inc. v. Chugai Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by ''whatever characteristics sufficiently distinguish it'').
Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, the breadth of the claims reasonably encompasses:
an enormous genus of about 1x10^6 human and non-human animal subjects to be treated by the method [parameter 1];
an enormous genus of anatomically and functionally distinct target cells, and tissues thereof, to which the pharmaceuticals is/are to be administered [parameter 2];
an enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject [parameter 3];
an enormous genus of structurally and functionally different pharmaceutical formularies comprising the enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject [parameter 4];
a very large genus of different nucleic acid vectors, including, but not limited to, plasmids, viral vectors, naked DNA, liposomes, cosmids, bacterial chromosomes, bacteriophages, transposons, and rAAV serotypes having different cell-type specific tropisms [parameter 4];
an enormous genus of structurally and functionally undisclosed corresponding protein, nucleic acid, and cellular pharmaceuticals dosages [parameter 5]; and
an enormous genus of anatomically distinct administration routes [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”.
In the instant case, Applicant seeks to monopolize an entire class of treating blindness or vision loss without satisfying the real-world scientific and clinical nexus of the required:
protein dosage(s) of the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes;
nucleic acid vector dosage(s) of the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes; and/or
genetically modified host cell dosage(s) of the enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes,
so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s) of ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62), as required by the claims.
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, Applicant seeks to claim for themselves an entire universe of structurally undisclosed pharmaceutical formularies.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
Applicant is reminded that MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
8. Claims 43-62 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.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
The nature of the invention involves one of the most complex and unpredictable areas of medicine molecular biology - gene therapy treatment.
The invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology." Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The gene therapy art is unpredictable, as manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells, routes of administration, the transient and unpredictable expression of the transgenes in target cells, the specific genes to be used for a treatment, the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
However, the claims do not even require the protein, expression vector, and/or genetically modified host cell to deliver the light-sensitive protein to be expressed in an ocular cell, let alone a rod or cone cell. Rather, the breadth of the claims allows for the light-sensitive protein to be expressed anywhere in the subject’s body, e.g. colon, intestine, kidney, lung, heart, etc… The instant claims and specification fail to disclose how administering the broad genus of proteins, expression vectors, bacteriophages, plasmids, viral vectors, naked DNAs, and/or host cells to the subject via the enormous genus of anatomically distinct routes and enormous genus dosages will necessarily and predictably deliver said broad genus of protein, expression vectors, bacteriophages, plasmids, viral vectors, naked DNAs, and/or host cells to an ocular, more specifically, retinal, cell when such cannot cross the blood-brain barrier.
Sasse et al (Circulation: Arrhythmia and Electrophysiology 4(5): 598-600, available October 1, 2011; of record in parent application 16/573,321) taught that the artisan would need to overcome numerous technical hurdles before the optogenetic system would work, including:
"the most complex problem will be to identify a safe strategy for efficient and long-lasting cell transplantation or gene transfer that allows in vivo application of ChR2 in native nontransgenic hearts";
"[T]he excitation light to activate ChR2 (470 nm) as well as the red-shifted variants from other species such as VChRl from Volvox carteri or MChRl from Mesostigma viride (530 nm) does not penetrate deep into tissue; therefore, light stimulation through the chest wall will not be feasible”;
"[E]picardial stimulation was used to effectively stimulate ChR2-expressing mouse hearts, 11 but it remains unclear whether this would be sufficient to activate transplanted cells deep within the myocardium"; and
"electroluminescent foils and wires, which ... currently do not provide enough light intensity ... ".
Nussinovitch et al (Nature Biotechnology 33(7): 750-754, July 2015; of record in parent application 16/573,321) taught an example of cardiac optogenetics requiring the open-chest procedure (Figure 1b), wherein said rat is splayed out on its back and immobilized in order to be outfitted with the optical fiber (Figure 1c). Alternatively, the entire heart is removed from the subject, and being isolated from said subject, then illuminated (Figure 2a). Such are not real-world conditions in which to perform cardiac optogenetic therapy on human patients, nor the enormous genus of vertebrate and invertebrate animal subjects, in need of treatment. Nussinovitch et al taught that “the density and uniformity of the transduced areas may affect the light-intensity threshold required for pacing” (pg 753, col. 2), a deficiency the instant application fails to overcome. Furthermore, “[I]t remains unknown whether blue light can sufficiently penetrate cardiac muscle and blood to efficiently activate transduced cells in humans. Improved versions of [channelrhodopsin] (with superior photosensitivity and higher currents) or other light-sensitive proteins responsive to light wavelengths with better tissue penetrance may be required for optogenetic pacing in…human patients.” (pg 753, col. 2, conclusory ¶).
Nussinovitch et al taught that “Translating these findings to the in vivo settings, first to small and large animal models and eventually to the clinic would require overcoming major challenges. This would also necessitate prolonged survival of the transplanted cells, long-lasting expression of the Arch transgene in the engrafted cells, and the efficient coupling of the engineered cells with host cardiomyocytes also in the intact heart. Moreover, it is not clear whether the electrotonic currents generated, which were sufficient to suppress excitability in the monolayers or cell clusters, will also be large enough to affect cardiac activity also in vivo. Another potential caveat to clinical translation may be the transient hyperexcitable state noted post-illumination at the treated region that may be proarrhythmogenic. Finally, it is not clear whether the monochromatic light sources used to activate the hyperpolarizing light-sensitive proteins can sufficiently penetrate through cardiac muscle or blood to efficiently influence the transduced cells that may be embedded deep within the myocardium. (pg 12, col.’s 1-2, joining¶).“Translation of these initial in vitro results in co-culture studied into the clinics would require significant technological developments and overcoming significant challenges.” (pg 12, col. 2, Conclusion).
Jiang et al (EP Eurospace 20(11): 1741-1749, 2018; of record in parent application 16/573,321) is considered relevant post-filing art for having taught that before optogenetics can be clinically applied, safety issues must be resolved, including the immunity induced by the virus, the duration of photosensitive protein expression, the damage caused by light, and the optimal implant device (pg 1746, col. 1). Direct myocardial injections may increase the efficiency of local transfection but decrease the efficiency at remote myocardial sites, which is a limitation of target cell activation/inhibition in these remote areas. Multipoint injection (as per the instantly claimed invention) may expand the transfected area but also increase myocardial injury (pg 1746, col. 2). There are multiple challenges for the application of optogenetics in heart research, including:
i) safe and effective gene delivery;
ii) long-term expression of photosensitive proteins;
iii) optimization of devices such as optical device, sufficient optical power, light penetration, fibre or wireless devices, and detectors;
iv) unscattered and unattenuated exogenous light stimulation; and
v) location of the implanted stimulator and direction of illumination without interference from lung activity (pg 1747, col. 1, conclusory ¶).
Entcheva et al (Nature Reviews Cardiology 18: 349-367, 2021; of record in parent application 16/573,321) is considered relevant post-filing art for having taught that clinical translation of cardiac optogenetics, including new optical therapies for rhythm control, remains an aspirational prospect [emphasis added] (syn. as of 2021 not yet achieved; Abstract). The immediate translation of cardiac optogenetics is for outside-the-body deployment (pg 352, col. 1). Long- term optogenetic pacing with an implantable device has not yet been demonstrated [emphasis added] (syn. as of 2021 not yet achieved) in an awake animal (pg 355, col. 2).
Optical pacing would be [emphasis added] (syn. as of 2021 not yet achieved) an attractive alternative to electronic pacemakers (pg 355, col. 2).
Low-energy optogenetic pacing could emerge [emphasis added] (syn. as of 2021 not yet achieved) as a disruptive technology if optogenetic transduction and light delivery are safe and minimally invasive (pg 357, col. 2)
Light penetration into the myocardium is an important consideration for the clinical translation of optogenetic cardioversion or defibrillation, especially for the ventricles. Additional work is certainly needed to better understand light–matter interactions within the context of using distributed light for optogenetic cardioversion. (pg 359, col. 1)
While rhythm management using optogenetics is particularly promising for ultra- low- energy cardioversion. However, the implementation could be challenging due to the substantial spatiotemporal data that would need to be processed in quasi-real-time by an implanted device (pg 359, col. 2)
Challenges in translating cardiac optogenetics to the clinic are substantial and confounded by the obvious need for new therapies to be better than the current standard of care.
Technical challenges for translation reside in the methods used to deliver opsins and light to the heart. To achieve opsin expression in patients would require gene therapy via AAV-based vectors or similar, and a minimally invasive procedure would be required for cardiac site- specific transduction of these vectors. Efficient expression of opsins in the presence of neutralizing antibodies in the host against the viral vectors is a challenge as is the risk of cardiotoxicity associated with viral capsids and opsins, as covered in a previous review on the current state of human gene therapy.
The possibility for the opsins to trigger an immune response when expressed in the human heart deserves serious investigation before clinical deployment. Engaging resident opsins with light is further confounded by the vigorous contraction of the heart and the lack of a stabilizing surface to anchor an optical device. Visible light absorption by the blood remains a challenge that has motivated recent work to develop long- wavelength opsins, up- conversion of nanoparticle mediators for blue-light opsins, and other performance- boosting strategies. Finally, to leverage fully the cell-specific optogenetic control of cardiac function, the palette of well- characterized, cell-specific promoters would need to be expanded, at least to the level of what is currently available for neuroscience.
Thus, the breadth of the claimed invention is not yet enabled for in vivo practice in the enormous genus of about 1x10^6 human and non-human animal subjects. Neither the prior art nor the instant specification makes up for the deficiencies in the prior art, nor solve the technological problems, in order to practice the instantly claimed invention.
Applicant’s specification fails to adequately describe the necessary and sufficient technology(ies) and method steps required to treat the vast, essentially unlimited, disease, disorder, or condition located essentially anywhere anatomically in said enormous genus of extant human and non-human mammalian subjects “in need” upon administration via the enormous genus of anatomically distinct routes of the enormous genus of structurally undisclosed, different variants of protein, nucleic acid, and/or host cell pharmaceuticals.
The specification is silent to the dosage(s) of the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is to be administered to the subject so as to necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
The specification fails to make up for deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
The specification is silent to the dosage(s) of said enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said protein, including bacterial host cells, fungal host cells, plant host cells, insect host cells, non-human animal host cells, and human host cells that is/are to be administered to the subject so as to necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
The specification fails to make up for deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
The specification is silent to the dosage(s) of said enormously vast genus of nucleic acids encoding and expressing said protein, including bacterial artificial chromosomes, cosmids, phages, naked DNA, plasmids, viral vectors, and transposons that is/are to be administered to the subject so as to necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62) in the enormous genus of subjects, including essentially all animal life.
The specification fails to make up for deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, the breadth of the claims reasonably encompasses:
an enormous genus of about 1x10^6 human and non-human animal subjects to be treated by the method [parameter 1];
an enormous genus of anatomically and functionally distinct target cells, and tissues thereof, to which the pharmaceuticals is/are to be administered [parameter 2];
an enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject [parameter 3];
an enormous genus of structurally and functionally different pharmaceutical formularies comprising the enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, that is/are to be administered to the subject [parameter 4];
a very large genus of different nucleic acid vectors, including, but not limited to, plasmids, viral vectors, naked DNA, liposomes, cosmids, bacterial chromosomes, bacteriophages, transposons, and rAAV serotypes having different cell-type specific tropisms [parameter 4];
an enormous genus of structurally and functionally undisclosed corresponding protein, nucleic acid, and cellular pharmaceuticals dosages [parameter 5]; and
an enormous genus of anatomically distinct administration routes [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”.
In the instant case, Applicant seeks to monopolize an entire class of treating blindness or vision loss without satisfying the real-world scientific and clinical nexus of the required:
protein dosage(s) of the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes;
nucleic acid vector dosage(s) of the enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes; and/or
genetically modified host cell dosage(s) of the enormously vast genus of about 3x10^7 structurally and functionally distinct host cells expressing said enormous genus of about 2x10^23 structurally and functionally undisclosed protein variants for each SEQ ID NO, respectively, to be administered to the genus of about 1x10^6 human and non-human animals via the enormous genus of anatomically distinct routes,
so as to necessarily and predictably achieve a real-world, clinically meaningful, therapeutic result(s) of ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62), as required by the claims.
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, Applicant seeks to claim for themselves an entire universe of structurally undisclosed pharmaceutical formularies.
“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 Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the enormously vast claimed genus of pharmaceutical formularies administered to the enormously vast genus of subjects via the enormous genus of anatomically distinct routes at the enormously vast genus of structurally undisclosed dosages so as to necessarily and predictably able to achieve a real-world, clinically meaningful treatment, including the recited therapeutic effects of meaningfully ameliorating blindness or vision loss of the subject in need, thereby improving or restoring light sensitivity of the subject (Claim 43), including fully or partially restoring or enhancing vision of the subject (Claim 61) and/or restoring or enhancing the photosensitivity of the retinal neurons in the subject, and/or photosensitivity of a retina or a portion thereof of the subject (Claim 62).
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to extrapolate the results provided in the instant specification of intravitreal administering the AAV2 vector encoding sVEGFRv-1 to the larger genus of AAV capsid serotypes having different cellular tropisms, the enormous genus of anatomically different administration routes, and the enormous genus of rAAV dosages reasonably encompassed by the claims. Neither the specification nor the claims provide the appropriate nucleic acid vector or viral dosage to be administered in the plurality of possible intravenous, intracranial, intraperitoneal, intramuscular, subcutaneous, intramuscular, intrarectal, intravaginal, intrathecal, intratracheal, intradermal, or transdermal injection, by oral or nasal administration means that would reasonably be expected by the ordinary artisan to necessarily and predictably achieve a clinically meaningful, real-world therapeutic result to treat retinal disease and photoreceptor loss present in achromatopsia.
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible nucleic acids disclosed), routes of administration (as recited, the independent claim does not even require direct administration to the eye tissue), the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), and the unsuitability of many animal models of human diseases, etc…, all critical for the success of a gene therapy method.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013; of record in parent application 16/573,321) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016; of record in parent application 16/573,321) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Those of ordinary skill in the art would immediately recognize that the instant specification fails to establish the nexus between the broad genus of AAV vectors, the enormous genus of AAV vector dosages, and the corresponding enormous genus of anatomically distinct administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in the enormous genus of human and non-human animal subjects encompassed by the claimed methods.
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The specification fails to make up for deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the enablement requirements under 35 U.S.C. 112, first paragraph.
Applicant is reminded that MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
9. Claims 43-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-11 of U.S. Patent No. 11,858,969 in view of Sengupta et al (Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina, EMBO Molecular Medicine 8(11): 1248-1264; 2016).
‘969 claims a method of delivering a protein or nucleic acid encoding said protein to a subject, wherein said protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO’s 5-19, 21-42, 44, 46-49, 51-56, 58, 60-71, 73-74, 76-139, 141-147, 149-154, 157-175, and 178-196.
‘969 claims wherein the protein or nucleic acid encoding said protein is administered to ocular cells, e.g. via intraocular injection, intravitreal injection, subretinal injection, or intravenous delivery, thereby resulting in the expression of said protein or nucleic acid encoding said protein in the retinal cells of the eye, including electrically active cells of the eye.
‘969 does not claim wherein the method of delivery improves or restores light sensitivity of the subject, thereby ameliorating blindness or vision loss of the subject.
Either the instantly recited functional properties are inherent properties of the thus-administered, e.g. intraocular, intravitreal, subretinal, and/or intravenous injection (claims 8-9) SEQ ID NO proteins of ‘969, or they are not, and something must change.
Furthermore, prior to the effective filing date of the instantly claimed invention,
Sengupta et al is considered relevant prior art for having taught methods of ameliorating or restoring vision loss in a mouse subject, the method comprising the step of administering by intravitreal injection (e.g. pg 1259, col. 1, Methods, “Intravitreal AAV injections in mice”) a rAAV virus expressing a light-sensitive protein, e.g. ReaChr.
To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and enablement rejections.
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.
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.
Instant claims are considered an obvious variant of the ‘969 patented claims.
Conclusion
10. Claims 43-62 are rejected.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights