Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 8, 2025 has been entered.
Detailed Action
This action is in response to the papers filed September 8, 2025.
Amendments
Applicant's response and amendments, filed September 8, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 1-35 and 37, and amended Claims 36 and 53.
Claims 36 and 38-53 are pending and under examination.
Priority
This application is a 371 of PCT/US2020/036600 filed on June 8, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/859,369 filed on June 10, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on September 8, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
1. The prior objection to Claim 36 is withdrawn in light of Applicant’s amendment to the claim.
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.
2. Claims 36 and 38-53 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.
Applicant has amended Claim 36 to recite a nucleotide sequence comprising a concatenation of:
i) a first DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame;
ii) a second DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame; and
iii) a third DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame.
The term “a… DNA sequence” is a relative term which renders the claim indefinite. The term “a… DNA sequence” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
While the Figures 8A and 28A illustrate a cartoon of where a “3 peak” enhancer(s) exists upstream of the GATA1 gene, neither the Figure nor the specification actually disclose the exact location(s) nor the nucleotide sequence(s) of said “3 peak” enhancer(s). It would seem that the first, second, and third regions may each contain 1000 nucleotides or more.
Figure 8A clearly illustrates, for example, a DNA region that is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame, yet comprises both more than one distinct open (peaks) DNA regions and more than one distinct closed (troughs) DNA regions, as shown below:
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Thus it is unclear which “open” domain(s) or subdomain(s) is/are to be present in the claimed “first DNA sequence”, “second DNA sequence”, and “third DNA sequence”, respectively, that is then to be concatenated.
Figure 8A clearly discloses a multitude of different peaks (syn. “open”) positioned upstream of and within 7kb of the boundary of the endogenous human GATA1 open reading frame, for example, including, but not limited to, the arrows shown below:
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Figure 8A evidences that different DNA sequences are “open” (peaks vs troughs) in different types and/or stages of differentiating human erythroid cells, for example, as shown below:
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The recitation implies a genus of different reference “differentiating human erythroid cells” by which “open chromatin structure” is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
If there are multiple ways to measure “open chromatin structure”, to wit, different types and/or stages of “differentiating human erythroid cells”, yet each yields a different result, then the claimed “first DNA sequence”, “second DNA sequence”, and/or “third DNA sequence”, respectively, may be indefinite because it is unclear which type(s) and/or stage(s) of “differentiating human erythroid cells” is to be referenced, and the corresponding “first DNA sequence”, “second DNA sequence”, and/or “third DNA sequence” is to be present in the claimed concatenation to determine infringement.
The claims do not recite, and the specification fails to disclose, the metes and bounds of the DNA sequence to which “a first DNA sequence”, “a second DNA sequence”, and “a third DNA sequence” refers.
The claimed DNA region positioned upstream of the boundary of the human GATA1 open reading frame is at least 7000 nucleotides in length, and thus is composed of a multitude of subsequences.
The recited limitations each encompass nucleic acids of at least 7000 nucleotides in length, or something as small as just 2 nucleotides.
In light of Figure 8A, the recited “DNA sequence” would each appear to encompass a range of nucleotide lengths, e.g. about 500 to about 1500 nucleotides (SEQ ID NO:11 is 501 nucleotides, SEQ ID NO:38 is 1179 nucleotides); however, instant Claim 36 is broader in scope than the disclosed SEQ ID NO’s.
The specification discloses a hematopoietic enhancer minigene construct comprising a concatenation of four distinct regulatory elements, to wit, a -3kb hematopoietic enhancer, a GATA motif, a CACCC box, and the first intron of GATA1 (e.g. pg 45, lines 2-3).
However, the specification fails to disclose the nucleotide sequence of the -3kb hematopoietic enhancer, and thus is uninformative of how this sequence relates to the “first DNA sequence”, the “second DNA sequence”, and/or the “third DNA sequence”. For example, is this the entirety of the “DNA sequence”, or is it only a fragment of the “DNA sequence”?
Further, those of ordinary skill in the art would immediately recognize that the GATA motif and CACCC box, individually and respectively, are mere fragments of (4/500; 4/1500) the claimed “DNA sequence”.
The claim is considered indefinite because it is unclear is Applicant is requiring concatenation of the entire first, second, and third regions, respectively, or if the concatenation only requires some fragment(s) of the first, second, and third regions, respectively, e.g. just the GATA motif and CACCC box, for example.
The claim is considered indefinite because it is unclear which one or more fragment(s) of the first, second, and third regions, respectively, are to be concatenated, for example.
Applicant has amended Claim 53 to recite:
“the first sequence is the first sequence in SEQ ID NO:62”;
“the second sequence is the second sequence in SEQ ID NO:62”; and
“the third sequence is the third sequence in SEQ ID NO:62”.
SEQ ID NO:62 is 7503 nucleotides in length.
To what first, second, and/or third sequences in SEQ ID NO:62, per “the….sequence in SEQ ID NO:62”, is Applicant referring??
The claim fails to recite, and the specification fails to disclose, what is “the first sequence”, “the second sequence”, and/or “the third sequence” in SEQ ID NO:62.
The functional language of Claim 53 suffers the same deficiencies as the functional language of Claim 36.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that the specification provides Figure 8A, and thus the ordinary artisan would understand the location of GATA1 open reading frame, and the three sequences with open chromatin structure.
Applicant’s argument(s) has been fully considered, but is not persuasive. Figure 8A is merely an illustration. The instant specification and Figure 8A fail to disclose the nucleotide sequences of the claimed first, second, and third DNA sequences.
Applicant argues that Buenrostro et al (2013; of record in IDS) depicts open or active chromatin in Figure 1 (ATAC-seq peak intensities).
Applicant’s argument(s) has been fully considered, but is not persuasive. Buenrostro et al (Figure 1) and instant Figure 8A are merely illustrations. Neither Buenrostro et al, the instant specification, nor instant Figure 8A teach/disclose the nucleotide sequences of the claimed first, second, and third DNA sequences.
Applicant argues that it is incorrect in stating “each region seems to have subdomains that are “closed”, while other subdomains are “open”.
Applicant’s argument(s) has been fully considered, but is not persuasive. Figure 8A clearly illustrates, for example, a DNA region that is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame, yet comprises both more than one distinct open (peaks) DNA regions and more than one distinct closed (troughs) DNA regions, as shown below:
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Thus it is unclear which “open” domain(s) or subdomain(s) is/are to be present in the claimed “first DNA sequence”, “second DNA sequence”, and “third DNA sequence”, respectively, that is then to be concatenated.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
3. Claim 53 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.
Applicant has amended Claim 53 to recite:
“the first sequence is the first sequence in SEQ ID NO:62”;
“the second sequence is the second sequence in SEQ ID NO:62”; and
“the third sequence is the third sequence in SEQ ID NO:62”.
SEQ ID NO:62 is 7503 nucleotides in length.
To what first, second, and/or third sequences in SEQ ID NO:62, per “the….sequence in SEQ ID NO:62”, is Applicant referring??
The claim fails to recite, and the specification fails to disclose, what is “the first sequence”, “the second sequence”, and/or “the third sequence” in SEQ ID NO:62.
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.
Response to Arguments
Applicant argues that SEQ ID NO:62 is named “R50 3 peak enhancer”, as illustrated in Figure 9D.
Applicant’s argument(s) has been fully considered, but is not persuasive. While Figure 9D illustrates the construct comprises a “peak3” DNA sequence of 350 nucleotides, a “peak2” DNA sequence of 385 nucleotides, and a “peak1” sequence of 796 nucleotides, neither the specification nor the Figure discloses the nucleotide sequences of said first, second, and third peak DNA sequences, respectively.
While Figure 9D labels “peak3”, “peak2”, and “peak1” in the illustration, Figure 8A fails identify which peak is “peak3”, as opposed to “peak2”, as opposed to “peak1”. A keyword search of the specification fails to retrieve “peak3”, “peak2”, and “peak1”, and thus, here too, Figure 9A is uninformative to “the first sequence”, “the second sequence”, and “the third sequence”, each recited at a high level of generality, and the specification fails to disclose the nucleotide sequences of “peak3”, “peak2”, and “peak1” in SEQ ID NO:62, respectively.
The specification fails to disclose the nucleotide sequences of “the first”, “the second”, and “the third” sequences, respectively, in SEQ ID NO:62.
Rather, SEQ ID NO:62 is merely disclosed as a nucleotide sequence that is 7503 nucleotides in length.
Claim 53 recites “the first sequence”, “the second sequence”, and “the third sequence” at a high level of generality, and thus the metes and bounds of the “the first sequence”, “the second sequence”, and/or “the third sequence” in SEQ ID NO:62 that is/are to be present in the claimed concatenation, respectively, is indefinite.
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.
4. Claim(s) 36 and 38-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has amended Claim 36 to recite a nucleotide sequence comprising a concatenation of:
i) a first DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame;
ii) a second DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame; and
iii) a third DNA sequence which i) has open chromatin structure in differentiating
human erythroid cells, and ii) is positioned upstream of and within 7 kb of the boundary of the endogenous human GATA1 open reading frame.
Applicant has amended Claim 53 to recite:
“the first sequence is the first sequence in SEQ ID NO:62”;
“the second sequence is the second sequence in SEQ ID NO:62”; and
“the third sequence is the third sequence in SEQ ID NO:62”.
SEQ ID NO:62 is 7503 nucleotides in length.
To what first, second, and/or third sequences in SEQ ID NO:62, per “the….sequence in SEQ ID NO:62”, is Applicant referring??
The claim fails to recite, and the specification fails to disclose, what is “the first sequence”, “the second sequence”, and/or “the third sequence” in SEQ ID NO:62.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
Substituting a first limitation(s) described only using functional language, to wit:
human GATA1 enhancer (hG1E) element (prior Claim 36), and
the 3 regions of DNA with open chromatin that are positioned upstream of and within at least 7 kb of the boundary of the human GATA1 open reading frame (prior Claim 37),
for a second limitation described only using functional language, to wit:
a first, second, and third region of DNA which has open chromatin structure in differentiating human erythroid cells, and b) which is positioned upstream of and within at least 7 kb of the boundary of the endogenous human GATA1 open reading frame (newly amended Claim 36),
does not overcome the issue of lack of adequate written description.
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 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).
While the Figure 28A illustrates a cartoon of where a “3 peak” enhancer exists upstream of the GATA1 gene, neither the Figure nor the specification actually disclose the exact location(s) nor the nucleotide sequences of the first, second, and third DNA sequences of said “3 peak” enhancer.
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The claims would seem to encompass a “hG1E” enhancer having a nucleotide sequence of about 500 nucleotides, for example.
However, as evidenced by Figure 8A, there are multitude of structurally different DNA sequences positioned upstream of and within 7kb of the boundary of the endogenous human GATA1 open reading frame having “open chromatin structure”, depending upon the referenced differentiating human erythroid cell from which one assays, that when concatenated may yield a synthetic enhancer element of about 500 nucleotides in length.
While the specification discloses heterologous hematopoietic enhancers such as SEQ ID NO’s 10, 11, 12, 38, and 39 [00105-110], the specification discloses the claimed synthetic element need only be at least 60% identical to any one referenced SEQ ID NO.
4^500 is an enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids.
(https://www.calculator.net/exponent-calculator; last visited March 10, 2025).
The specification discloses the hG1E element has the functional property of being responsible for erythroid-specific expression of GATA1 (e.g. [00298]).
While the specification discloses heterologous hematopoietic enhancers such as SEQ ID NO’s 10, 11, 12, 38, and 39 [00105-110], such are not disclosed to be the hG1E enhancer element. Further, the specification fails to disclose a common core structure of SEQ ID NO’s 10, 11, 12, 38, and 39 that are necessary and sufficient to achieve the functional property of being a hematopoietic enhancer, let alone something that is shared with the structurally undisclosed hG1E enhancer element.
The term “region of DNA” is a relative term which renders the claim indefinite. The term “region of DNA” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
While the Figures 8A and 28A illustrate a cartoon of where a “3 peak” enhancer exists upstream of the GATA1 gene, neither the Figure nor the specification actually disclose the exact location(s) nor the nucleotide sequence of said “3 peak” enhancer. It would seem that the first, second, and third regions may each contain 1000 nucleotides or more.
Further, each region seems to have subdomains that are “closed”, while other subdomains are “open”, respectively, and thus it is unclear which “open” subdomain is to be present in the claimed concatamer.
The claims do not recite, and the specification fails to disclose, the metes and bounds of the ‘region’ of DNA. The recited “region of DNA” would appear to encompass a range of nucleotide lengths, e.g. about 500 to about 1500 nucleotides (SEQ ID NO:11 is 501 nucleotides, SEQ ID NO:38 is 1179 nucleotides).
The specification discloses a hematopoietic enhancer minigene construct comprising a concatenation of four distinct regulatory elements, to wit, a -3kb hematopoietic enhancer, a GATA motif, a CACCC box, and the first intron of GATA1 (e.g. pg 45, lines 2-3).
However, the specification fails to disclose the nucleotide sequence of the -3kb hematopoietic enhancer, and thus is uninformative of how this sequence relates to the “first region of DNA”, the “second region of DNA”, and/or the “third region of DNA”. For example, is this the entirety of the “region of DNA”, or is it only a fragment of the “region of DNA”?
Further, those of ordinary skill in the art would immediately recognize that the GATA motif and CACCC box, individually and respectively, are mere fragments of (4/500; 4/1500) the claimed “region of DNA”.
The claim is considered indefinite because it is unclear is Applicant is requiring concatenation of the entire first, second, and third regions, respectively, or if the concatenation only requires some fragment(s) of the first, second, and third regions, respectively, e.g. just the GATA motif and CACCC box, for example.
Moriguchi et al (The Human GATA1 Gene Retains a 5′ Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts, Molecular and Cellular Biology 25(10):1825-1837, 2015) is considered relevant prior art for having taught a nucleic acid sequence comprising:
a) a sequence encoding a human GATA-binding factor 1 (GATA1) polypeptide; and
b) a human GATA1 enhancer element.
The BAC clones comprise the entire GATA1 locus, plus additional sequences upstream and downstream of the GATA1 locus (e.g. pg 1826, col. 1, “a 183-kb hGATA1 BAC (hG1B) DNA clone that harbors the hGATA1 genomic locus plus extensive flanking sequences”; Figure 1A, 80kb upstream and 116kb downstream of hGATA1 locus).
Moriguchi et al differ from the instant claims in that they teach an insulator element located about 29 kb upstream of the GATA1 open reading frame (e.g. Abstract).
With respect to Claim 53, SEQ ID NO:62 is 7503 nucleotides in length, and is disclosed to comprise an IRES sequence operably linked to a nucleotide sequence encoding GFP and three hematopoietic enhancer elements (e.g. pg 66).
However, the specification fails to identify which nucleotides of SEQ ID NO:62 encode:
i) the IRES;
ii) the GFP;
iii) the first hematopoietic enhancer element;
iv) the second hematopoietic enhancer element; and
v) the third hematopoietic enhancer element, respectively.
Reference SEQ ID NO:62 is uninformative as it pertains to the nucleotide sequence(s) [structure(s)] of the claimed first, second, and third hematopoietic enhancer elements, respectively, let alone concatenations thereof.
The claims do not recite, and the specification fails to disclose, a first nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that does not have the functional property of being a hG1E enhancer element, as opposed to a second nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that necessarily and predictably has the functional property of being a hG1E enhancer element, for example.
The claims do not recite, and the specification fails to disclose, a first nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that does not have the functional property of being responsible for erythroid-specific expression of GATA1, as opposed to a second nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that necessarily and predictably has the functional property of being responsible for erythroid-specific expression of GATA1, for example.
The claims do not recite, and the specification fails to disclose, how to transform or otherwise modify a first nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that does not have the functional property of being responsible for erythroid-specific expression of GATA1, into a second nucleic acid sequence of the enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that now necessarily and predictably has the functional property of being responsible for erythroid-specific expression of GATA1, for example.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994).
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’).
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. These claims are usually handled in Technology Center 1600. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id. The Amgen decision will be added to the MPEP in due course.
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.
In the instant case, the specification fails to disclose the structural identity of hG1E enhancer element, let alone a hG1E element that necessarily and predictably has the functional property of being responsible for erythroid-specific expression of GATA1.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the hG1E enhancer is a nucleotide sequence composed of a combination of four different nucleotide bases, A, G, C, and T, let alone may be located somewhere as much as 10,000 nucleotides upstream of the hGATA1 open reading frame, does not tell you anything about the actual nucleotide sequences [structures] that objectively satisfy “hG1E”, as opposed to those nucleotide sequences that do not objectively satisfy “hG1E”, nor the actual nucleotide sequences [structures] that necessarily and predictably have the functional properties of being an enhancer, let alone being responsible for erythroid-specific expression of GATA1.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the claims would appear to reasonably encompass an enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that are to necessarily and predictably have the functional property of being an enhancer, let alone an enhancer responsible for erythroid-specific expression of GATA1.
“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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that the specification provides the source sequence.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, while Figure 9D labels “peak3”, “peak2”, and “peak1” in the illustration, Figure 8A fails identify which peak is “peak3”, as opposed to “peak2”, as opposed to “peak1”. A keyword search of the specification fails to retrieve “peak3”, “peak2”, and “peak1”, and thus, here too, Figure 9A is uninformative to “the first sequence”, “the second sequence”, and “the third sequence”, each recited at a high level of generality, and the specification fails to disclose the nucleotide sequences of “peak3”, “peak2”, and “peak1” in SEQ ID NO:62, respectively.
The specification fails to disclose the nucleotide sequences of “the first”, “the second”, and “the third” sequences, respectively, in SEQ ID NO:62.
Rather, SEQ ID NO:62 is merely disclosed as a nucleotide sequence that is 7503 nucleotides in length.
The claimed “the first sequence”, “the second sequence”, and “the third sequence” are each recited at a high level of generality, and are broader in scope than the three hematopoietic enhancer elements of SEQ ID NO:62.
Applicant argues that the claims do not encompass about 1x10^301 structurally and functionally undisclosed nucleic acids that are to necessarily and predictably have the functional property of being an enhancer, let alone an enhancer responsible for erythroid-specific expression of GATA1. Rather, the claims are directed to only sequences found upstream of and within 7kb of the boundary of the endogenous human GATA1 open reading frame, and which have open chromatin structure in differentiating human erythroid cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims would seem to encompass a “hG1E” enhancer having a nucleotide sequence of about 500 nucleotides, for example. However, as evidenced by Figure 8A, there are multitude of structurally different DNA sequences positioned upstream of and within 7kb of the boundary of the endogenous human GATA1 open reading frame having “open chromatin structure”, depending upon the referenced differentiating human erythroid cell from which one assays, that when concatenated may yield a synthetic enhancer element of about 500 nucleotides in length.
While the specification discloses heterologous hematopoietic enhancers such as SEQ ID NO’s 10, 11, 12, 38, and 39 [00105-110], the specification discloses the claimed synthetic element need only be at least 60% identical to any one referenced SEQ ID NO.
Thus, the breadth of the claimed first, second, and/or third DNA sequence(s) would each appear to encompass an enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that are to be concatenated.
Instant Claim 36 and Claim 53 recitations are much broader in scope than SEQ ID NO:62.
Applicant argues that the limitation “open chromatin structure in differentiating human erythroid cells” is a structural description, and that “positioned upstream of and within at least 7kb of the boundary…” provides further structural description.
Applicant’s argument(s) has been fully considered, but is not persuasive. While “positioned upstream of and within at least 7kb of the boundary…” is structural, the limitation “open chromatin structure in differentiating human erythroid cells” is a functional property.
The claims would seem to encompass a “hG1E” enhancer having a nucleotide sequence of about 500 nucleotides, for example.
4^500 is an enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids.
The specification discloses the hG1E element has the functional property of being responsible for erythroid-specific expression of GATA1 (e.g. [00298]).
While the specification discloses heterologous hematopoietic enhancers such as SEQ ID NO’s 10, 11, 12, 38, and 39 [00105-110], such are not disclosed to be the hG1E enhancer element. Further, the specification fails to disclose a common core structure of SEQ ID NO’s 10, 11, 12, 38, and 39 that are necessary and sufficient to achieve the functional property of being a hematopoietic enhancer, let alone something that is shared with the structurally undisclosed hG1E enhancer element.
Applicant argues that the two different structural characteristics are provided in SEQ ID NO:62.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, SEQ ID NO:62 is 7503 nucleotides in length, and is disclosed to comprise an IRES sequence operably linked to a nucleotide sequence encoding GFP and three hematopoietic enhancer elements (e.g. pg 66).
However, the specification fails to identify which nucleotides of SEQ ID NO:62 encode:
i) the IRES;
ii) the GFP;
iii) the first hematopoietic enhancer element;
iv) the second hematopoietic enhancer element; and
v) the third hematopoietic enhancer element, respectively.
Reference SEQ ID NO:62 is uninformative as it pertains to the nucleotide sequence(s) [structure(s)] of the claimed first, second, and third hematopoietic enhancer elements, respectively, let alone concatenations thereof.
Applicant argues that the genus of possible nucleic acids does not apply to the claims because the claims require the three regions.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims fail to recite the nucleotide sequence of the first, second, and third regions, individually and respectively, that are then to be concatenated. Rather, such limitations are recited only using functional language.
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’).
5. The prior rejection of Claims 36, 38-51, and 53 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, is withdrawn in light of Applicant’s argument that there is no undue experimentation to perform chromatin analysis of a 7kb span of human genomic DNA, which the Examiner finds persuasive.
6. Claim 52 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 52 is directed to methods of treating Diamond-Blackfan Anemia in a subject, the method comprising the step(s) of administering to said subject a nucleic acid molecule comprising:
i) a sequence comprising a concatenation of a first, second, and third DNA sequence positioned upstream of and within 7kb of the boundary of the endogenous murine and human GATA1 open reading frames; and
ii) a sequence encoding a GATA1 polypeptide, as recited in Claim 36.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, indefinite, rejections.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the claimed nucleic acid molecule must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
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.
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 nucleic acid vector [parameter 2];
the structure(s) of regulatory element(s) [parameter 3];
the dosage to be administered [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the nucleic acid that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of human and non-human vertebrate animals, including fish, avian species, and mammals [00212].
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claimed methods are recited at a high level of generality for type of nucleic acid vector to be administered, said vectors including, but not limited to RNA molecules, plasmids, transposons, bacteriophages, cosmids, chromosomes, artificial chromosomes, viruses [00241], dendrimers, nanoparticles, liposomes, exosomes, or other synthetic vesicles [00249].
Parameter 3
The claimed methods are broad for reciting an enormously vast genus of about 1x10^301 structurally and functionally undisclosed nucleic acids that are to be concatenated in one or more combinations and/or subcombinations thereof, thereby resulting in a synthetic enhancer element.
See the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, indefinite, rejections.
Parameter 4
The claimed methods are recited at a high level of generality, failing to recite the dosage of the nucleic acid molecules to be administered to the subject, whereby said dosages may include, but are 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]).
The specification discloses the dosage will vary, according to the age, condition, and sex of the subject [00186], or provides a desired effect [00182], which itself is an arbitrary and subjective determination.
No reduction to practice of the claimed method(s) is disclosed.
Parameter 5
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