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
Status of Application, Amendments, and/or Claims
The Information Disclosure Statements (IDS) filed 24 July 2023, and 9 June 2026 have been entered. Applicant’s submission of a substitute specification in both marked-up and clean formats in compliance with 37 C.F.R. 1.52, 1.121(b)(3), and 1.125, filed 24 July 2023, is acknowledged.
Election/Restriction
In the response received on 9 June 2026, Applicant elected, without traverse, the invention of Group I, claims 1-2, 5-6, 10-12, 14-15, 18, 20 and 31-32, and the species:
A) wherein the plasminogen is Glu-Plg;
B) wherein the plasminogen comprises, consists of, or consists essentially of the amino acid sequence as set forth in SEQ ID NO: 2;
C) wherein the Fc region comprises, consists essentially of, or consists of the amino acid sequence as set forth in SEQ ID NO: 24;
D-b) wherein the plasminogen is covalently linked to the Fc region via a linker and the linker sequence is SEQ ID NO:23; and
E) wherein the nucleotide sequence that encodes a plasminogen comprises, consists of, or consists essentially of the nucleotide sequence as set forth in SEQ ID NO: 1.
Claims 3-4, 7-9, 13, 16-17, 19, 21, 24, 27, 30, 33-34 and 36 are cancelled. Claims 1-2, 5-6, 10-12, 14-15, 18, 20, 22-23, 25-26, 28-29, 31-32 and 35 are pending. Claims 22-23, 25-26, 28-29 and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 5-6, 10-12, 14-15, 18, 20 and 31-32 are under examination to the extent they read on the elected species. Claims 1-2, 5-6, 10-12, 18, 20 and 31-32 read on the elected species, and claims 14-15 are withdrawn as being drawn to a nonelected species.
Information Disclosure Statement
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.
Sequence Rules Compliance
The instant application is not fully compliant with the sequence rules, 37 CFR 1.821-1,825, because each disclosure of a sequence embraced by the definitions set forth in the rules is not accompanied by the required reference to the relevant sequence identifier (i.e., SEQ ID NO). This occurs in the specification at paragraphs [0101] [0104] [0208]. Compliance with the sequence rules is required.
Specification
The disclosure is objected to because of the following informalities:
In paragraph [0209], the text in bold font is not necessary.
Appropriate correction is required.
Claim Objections
Claims 5-6 and 12 are objected to because of the following informalities:
Claim 5 uses acronyms without first defining what they represent in the independent claims (e.g., “Plg”). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
In claim 6, the phrase “SEQ ID NOs: 2, 7, 9, 11, 13, 15, 16, 17, 18, 19 or 20” should be “SEQ ID NOs: 2, 7, 9, 11, 13, 15, 16, 17, 18, 19 and 20”; and the phrase “at least 75%, … at least 98%, at least 99% identical to …” should be “at least 75%, … at least 98%, or at least 99% identical to …”.
In claim 12, “having 60%, 65%, …identity” should be “having at least 60%, 65%, …identity”; and “having with 0 to 8 amino acid insertions, …” should be “with 0 to 8 amino acid insertions, …”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 2, 6, 10-12 and 32 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.
Regarding claims 2 and 32, the phrase "such as" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is suggested to amend claim 2 to recite “wherein the plasminogen is human plasminogen or a non-human primate plasminogen, and wherein the non-human primate is pig, mouse, rat, sheep, goat, horse, cow, cat, or dog”.
Regarding claims 6 and 10-12, the phrases “preferably” and “more preferably” render the claims indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d).
In claims 6 and 12, it is unclear whether the phrase in parentheses “(or a combination thereof)” is a required limitation.
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.
Claims 1-2, 5-6, 10-12, 18, 20 and 31-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A chimeric or fusion protein comprising plasminogen and an Fc region of an antibody,
wherein the plasminogen comprises an amino acid sequence of: i) a mammalian plasminogen or an active fragment thereof; or ii) a plasminogen comprising the amino acid sequence as set forth in any of SEQ ID NOs: 2, 7, 9, 11, 13 and 15-20 or that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence as set forth in any of SEQ ID NOs: 2, 7, 9, 11, 13 and 15-20; or iii) a plasminogen comprising an amino acid sequence as set forth in any of SEQ ID NOs: 2, 7, 9, 11, 13 and 15-20 with 0 to 8 amino acid insertions, deletions, substitutions, or a combination thereof; and
wherein the Fc region comprises: i) a native Fc sequence; or ii) an amino acid sequence comprising any one of SEQ ID NOs: 24-33 or that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence as set forth in one of SEQ ID NOs: 24-33; or iii) an amino acid sequence comprising any one of SEQ ID NOs: 24-33 with 0 to 8 amino acid insertions, deletions, substitutions, or a combination thereof,
does not reasonably provide enablement for the genus of chimeric or fusion proteins formed from the variants of the plasminogen sequences and the Fc sequences as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claims are broad and encompass chimeric or fusion proteins formed from variants of plasminogen and variants of an Fc region. For example,
“wherein the plasminogen comprises, consists or consists essentially of an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 7, 9, 11, 13, 15, 16, 17, 18, 19 or 20, or a sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence as set forth in any of SEQ ID NOs: 2, 7, 9, 11, 13, 15, 16, 17, 18, 19 or 20; or wherein the plasminogen comprises, consists or consists essentially of an amino acid sequence of SEQ ID NOs: 2, 7, 9, 11, 13, 15, 16, 17, 18, 19 or 20 with 0 to 8 amino acid insertions, deletions, substitutions or additions (or a combination thereof), preferably from 0 to 7, preferably from 0 to 6, preferably from 0 to 5, preferably from 0 to 4, preferably from 0 to 3, preferably from 0 to 2, preferably from 0 to 1 amino acid insertions, deletions, substitutions or additions (or a combination thereof).” (claim 6)
“wherein the Fc region of an antibody comprises, consists essentially of or consists of an amino acid sequence of any one of SEQ ID NOs: 24 to 33, or an amino acid sequence having 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any one of SEQ ID NOs: 24 to 33, or wherein the Fc region of an antibody comprises, consists essentially of or consists of an amino acid sequence of any one of SEQ ID NOs: 24 to 33 having with 0 to 8 amino acid insertions, deletions, substitutions or additions (or a combination thereof), preferably from 0 to 7, preferably from 0 to 6, preferably from 0 to 5, preferably from 0 to 4, preferably from 0 to 3, preferably from 0 to 2, preferably from 0 to 1 amino acid insertions, deletions, substitutions or additions (or a combination thereof)”. (claim 12)
The specification, however, fails to show evidence that these variants retain the activity of plasminogen or the structural characteristics of an Fc domain, nor teaches what activities/functions such molecules have. A person skilled in the art would not know how to make and/or use the broad genus of chimeric or fusion proteins as claimed.
Naturally occurring plasminogens and the active fragments derived therefrom are known in the art, for example, full-length plasminogens from human, pig, mouse, rat, sheet, goat, horse, cow, cat, dog, etc., and the active fragments derived therefrom by proteolytic cleavage, e.g., midi-, mini-, and micro-plasminogens. However, the specification does not provide sufficient teachings regarding making mutations up to 25% or even more (“consists essentially of” allows variations within the sequence) in the sequence of a naturally occurring plasminogen, e.g., SEQ ID NOs: 2, 7, 9, 11, 13 and 15-20. The specification does not teach where or what mutations can be made in the molecule such that it would retain the activity of plasminogen. The prior art does not provide compensatory guidance. There is no sufficient teaching regarding the correlation of structure and function. The variations in the sequence as encompassed by the present claims may lead to a protein unrelated to plasminogen. For example, hepatocyte growth factor isoform X3 (Prionailurus iriomotensis) shares 84% identity to the amino acid sequence of SEQ ID NO: 20 of the instant application (see sequence alignment provided, and it meets the structural requirement of the claimed plasminogen but is a totally different protein. Clearly, it requires undue experimentation to practice the invention as broadly claimed.
Similarly, the specification is not enabled to make and/or use variants of Fc domain that have up to 40% or even more mutations in the sequence of a native Fc domain as set forth in SEQ ID NOs: 24-33 (“consists essentially of” allows variations within the sequence). Such variants may lead to the loss of the structural characteristics, i.e., dimerization, of the Fc domain. One of ordinary skill in the art cannot envision the detailed structures of these variants and predict their activities/functions, thus would not know how to make and/or use the full scope of the claimed invention without undue experimentation.
Clearly, the instant specification does not enable one of skill in the art to make and/or use the broad genus of chimeric or fusion proteins. See In re Wands', 858 F.2d at 737, 8 USPQ2d at 1404. The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue" include, but are not limited to: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Given the breadth of the claims, in light of the predictability of the art as determined by the number of working examples, the level of skill of the artisan, and the guidance provided in the instant specification and the prior art of record, it would require undue experimentation for one of ordinary skill in the art to make and use the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 5-6, 10-12, 20, and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Koepf et al. (US 2015/0329845 A1, Pub Date: Nov. 19, 2015).
Koepf teaches compositions and methods for preparing a plasminogen, e.g., a human plasminogen [0007] [0036]. Koepf teaches that the plasminogen can be in a fusion protein form, such as an IgG Fc fusion protein (which forms a homodimer protein) [0068] [0098]. Koepf teaches the amino acid sequence of a plasminogen set forth in SEQ ID NO: 2, which is identical to SEQ ID NO: 2 of the instant application (also known as Glu-plasminogen) (see sequence alignment).
Regarding claim 12, the IgG Fc taught by Koepf meets the limitation for the Fc region that “consists essentially of” an amino acid sequence having at least 60% identity to any one of SEQ ID NOs: 24-33 (“consists essentially of” allows variations within the sequence).
Therefore, Koepf anticipates the instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Koepf et al. (US 2015/0329845 A1), as applied to claims 1-2, 5-6, 10-12, 20, and 31 above, and further in view of Murphy et al. (US 2005/0250185 A1, Pub. Date: Nov. 10, 2005).
Koepf teaches as set forth above. Koepf, however, does not teach the amino acid sequence of the Fc region as set forth in SEQ ID NO: 24 (the elected species).
Murphy teaches using human Fc (hFc) to make fusion proteins, wherein the hFc has the amino acid sequence as shown in SEQ ID NO: 14, which is identical to SEQ ID NO: 24 of the instant application (see sequence alignment).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the hFc taught by Murphy to make the plasminogen-Fc fusion protein of Koepf. One of ordinary skill in the art would have been motivated to do so, because Koepf teaches making a plasminogen fusion protein with the Fc region of IgG, and Murphy teaches the amino acid sequence of human Fc (hFc) that can be used for making Fc-fusion proteins. Therefore, the combined teachings provide a reasonable expectation of success in making a plasminogen-Fc fusion protein.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Koepf et al. (US 2015/0329845 A1), as applied to claims 1-2, 5-6, 10-12, 20, and 31 above, and further in view of Mulvihill et al. (U.S. Patent No. 5,648,254, Date of Patent: Jul. 15, 1997).
Koepf teaches as set forth above. Koepf also teaches that the plasminogen of the invention can be prepared by recombinant expression using, e.g., Chinese hamster ovary (CHO) or baby hamster kidney (BHK))-based recombinant expression system [0085]. Koepf, however, does not teach combining a plasminogen activator inhibitor (e.g., PAI-1) with the plasminogen.
Mulvihill teaches a method for producing plasminogen in a baby hamster kidney (BHK) cell by co-expressing plasminogen with a protease inhibitor, e.g., PAI-1 (see claims). Mulvihill teaches that plasminogen activation and subsequent degradation have limited the ability to produce recombinant plasminogen at reasonable levels, and that inhibition of plasminogen activation and/or plasmin activity by a co-expressed protease inhibitor, e.g., PAI-1, will ameliorate this problem (col. 7, lines 18-45). Mulvihill showed that the recombinantly produced secreted proteins and cell extracts contained full-length glu-plasminogen and PAI-1 (col. 17, lines 56-67).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the plasminogen of Koepf by co-expressing the plasminogen with a protease inhibitor, e.g., PAI-1. One of ordinary skill in the art would have been motivated to do so, because Koepf teaches a composition comprising plasminogen prepared by recombinant expression, and Mulvihill teaches that co-expressing PAI-1 with plasminogen can ameliorate plasminogen degradation and increase the production of the full-length protein. Therefore, the combined teachings provide a reasonable expectation of success in making a plasminogen composition.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674
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