DETAILED ACTION
Notice of 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 .
Status of Application
Claims 1-19 are pending and subject to examination on the merits.
Priority
The instant application is a 371 of PCT/CA2023/050770 filed 06 June 2023 which claims benefit of US Provisional application 63/349,242 filed 06 June 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03 February 2025 has been considered by the examiner. See initialed and signed PTO/SB/08.
Compliance with Sequence Rules
There are numerous Sequence compliance issues that are required to be addressed.
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set 37 C.F.R. § 1.831(b) ST.26. However, this application fails to comply with the requirements of 37 C.F.R. § 1.831-1.839.
ISSUE #1. The specification discloses several sequences but there is NO sequence listing on file. Applicants are required to file a sequence listing in compliance with 37 C.F.R. § 1.831-1.839, which are the rules directed to ST.26 sequence rules (See below).
ISSUE #2:
The following Figures/parts of the specification contain sequences that contain four or more specifically defined amino acids or ten or more specifically defined nucleotides without any corresponding SEQ ID NO:.
In Figure 2, amino acid sequences GGS[GGGS]6 and [GGGS]14GS are recited and each of these require a sequence identifier. This can be recited in the Brief Description of the Drawings sequence OR in the Figure itself.
Throughout the specification the peptides GGGS; GGS[GGGS]6 and [GGGS]14GS are recited, such as in paragraphs 0036, 0038, 0049-0052, 0067, 0074, with each occurrence requiring its own sequence identifier.
ISSUE #3: Claims 8 and 18-19 recite the sequences: GGGS; GGS[GGGS]6 and [GGGS]14GS, each of which requires its own sequence in the sequence listing and sequence identifier.
** Applicants must submit a sequence listing incorporating disclosed SEQ ID NOs: 1-7 as well as sequences for GGGS; GGS[GGGS]6 and [GGGS]14GS.
Applicants must amend the specification and/or claims and/or Drawings to identify the sequences appropriately by SEQ ID NO:.
Since the noted sequences are not in any sequence listing, Applicants must provide (1) a compliant sequence listing (ST.26) containing the requisite sequences in computer readable form (.xml), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification, claims and/or drawings to identify the identified sequences by SEQ ID NO:, and (5) an incorporation by reference statement with the new date of creation, sequence file name and size in bytes (not in kilobytes). – See also MPEP 2422.
Claim Objections
Claim1 is objected to because of the following informalities: the word “an” in between “with” and “amino acid” in the third line would improve grammar. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 6, 8, 10, 11, 18 and 19 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.
The claims are deemed indefinite as they are drawn to amino acid numbering of ADAMTS13; however, the claims do make clear what amino acids these numbers correspond to. For example, this enzyme is found in numerous mammalian species and said ADAMTS13 enzymes will necessarily differ in length and amino acid sequence(s). Thus, for example, position 380 or 848-894 in human ADAMTS13 may reflect a completely different amino acid or region as compared to rabbit ADAMTS13. Furthermore, there could be several deletion or insertion variants and thus the amino acids numbers which are stated in the claims might have no bearing upon a full length protein. It is suggested to insert a sequence number such as SEQ ID NO: to which the amino acids correspond to (e.g. are not limited to but correspond to) or to state in the claim that the numbering corresponds to the full-length, wild-type human ADAMTS13 protein.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-19 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
The claims are drawn to protease-resistant ADAMTS13 mutant proteins or nucleic acids encoding the same, wherein the ADAMTS13 mutant protein comprises a mammalian protein having one or more protease cleavage sites removed by amino acid replacement(s) rendering the mutant ADAMTS13 protein resistant to protease cleavage, while maintaining von Willebrand factor (VFW)-cleaving activity. Thus, the claims are drawn to a huge genus of ADAMTS13 enzymes from any mammalian source which further has variant amino acid sequences (and nucleic acid encoding sequences) which have site-directed amino acid replacement(s) for any or all proteases. This could be interpreted as replacing a single amino acid, two or more amino acids or entire regions, all of which then also must retain VFW-cleaving activity. It is noted there are hundreds of proteases, each of which have unique cleavage sites/requirements. For example, Bond states there are approximately 641 different proteases in vertebrates alone (See p. 1644, 2nd col., third bullet point). This, therefore, does not even account for prokaryotic or other non-vertebrate eukaryotic proteases. As noted, each different protease cleaves at unique and different sites, and as such, the very large ADAMTS13 metalloprotease having over 1400 amino acids (in the pre-form) is going to have a multitude of protease cleavage sites. For example, if one were to utilize Peptide Cutter from Expasy and run the 1427 amino acid human sequence through said program, as can be seen, there are hundreds if not thousands of unique results (See Results, cited herein). This demonstrates that the genus of variant ADAMTS13 mutant proteins being claimed is not only enormous but extremely variable. The specification, however, only details three specific examples to represent this entire huge and variable genus of claimed polypeptides in terms of structure and function, and that is substitution of amino acids W848-A894 and/or G1134-A1191 of SEQ ID NO: 1 (human ADAMTS13) with GGS[GGGS]6 and [GGGS]14GS, respectively, which results in ADAMTS13 resistant to the proteases plasmin, thrombin, FXIa, kallikrein, hPR3, Cathepsin G, and elastase; and a single amino acid replacement of I380G resulting in ADAMTS13 further making said ADAMTS13 resistant to neutrophil elastase, at least at that section of the enzyme. There are no other examples. While the specification also indicates Expasy Peptide Cutter was utilized to identify the potential protease cut sites in the ADAMTS13 protein that might be manipulated to render a protease resistant ADAMTS13, actually figuring out what did and did not work was essential. Thus, while these tools are available to one skilled in the art, the claimed genus is not represented by the two or three specific examples. The courts have made clear there needs to be a clear nexus between structure-function correlation requirement for the showing of possession of an invention regarding written description (or lack thereof) and limited disclosure/species. See Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336 (Fed. Cir. 2013):
A patent, however, “is not a reward for the search, but compensation for its successful conclusion.” Ariad, 598 F.3d at 1353 (quoting University of Rochester, 358 F.3d at 930 n.10). For that reason, the written description requirement prohibits a patentee from “leaving it to the . . . industry to complete an unfinished invention.” Id.
Finally, the claims suggest that the resultant ADAMTS13 mutant protein will be resistant to “protease cleavage”, interpreted to mean resistant to all proteases. This has not been demonstrated in the specification. As noted, the specification only suggests by replacing W848-A894 and/or G1134-A1191 of SEQ ID NO: 1 (and optionally further I380G) results in only a few select protease resistance to plasmin, thrombin, FXIa, kallikrein, hPR3, Cathepsin G, and elastase. This does not account for other proteases such as trypsin, chymotrypsin, papain, bromelain, etc., etc.
Claim 15 is 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 methods of treating and preventing diseases that result from blood clots by administering the protease resistant ADAMTS13, does not reasonably provide enablement for preventing diseases such as diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir.1988). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not ‘experimentation.’ ” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the relative skill of those in the art, (5) the predictability or unpredictability of the art, (6) the amount or direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of experimentation necessary.
1.Breadth of the claims.
In regards to the method of the invention and the breadth of the claims the broadest interpretation that applies is a methods of preventing diseases such as diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction.
2. The nature of the invention.
The invention is designed to provide treatment or prevention to those susceptible to various thrombi. However, it is entirely unclear how treating thrombi or the formation of thrombi is going to prevent disease such as diabetes which ultimately depend on the bodies ability to handle sugars and the distribution of insulin in response.
3. The state of prior art.
In regards to the treatment or prevention of the formation fo thrombi, the prior art provides evidence that this is possible. However, a method of prevention of diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction by inhibiting thrombi formation is not disclosed in the previous studies of such topic.
4. The relative skill in the art.
The relative skill in the art as it relates to the method of prevention of the noted diseases of the invention is characterized by that of a M.D. or Ph. D. level individual, however, this means nothing if the claimed invention is never attainable.
5. The level of predictability in the art.
Since there is not much known about the nature of preventing these diseases regarding inhibition of thrombi resulting in the prevention of diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction, the specification would need to have more detail as how to make and use the invention. One skill in the art would not be able to readily anticipate the effect of administering the protease resistant mammalian ADAMTS13 of the current invention in regard to preventing diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction.
6. The amount of guidance present.
The specification has not provided any guidance for the prevention of diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction is non-existent.
7. The existence of working examples.
The specification does not provide any information or examples that would suggest the applicants invention can be used to prevent diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction.
8. The quantity of experimentation necessary.
In the case of preventing diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction, one skilled in the art would be required to practice the invention since the specification has not shown to a person skill in the art how prevent diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction by administering protease resistant ADAMTS13.
Due to the large quantity of experimentation necessary to provide evidence that the claimed protease resistant mammalian ADAMTS13 of the invention will prevent diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction, the lack of guidance presented in the specification regarding the same, the absence of a working example directed to same, the unpredictable nature of the invention with regards to prevention, the state of the prior art not providing any evidence for any methods of prevention for diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction, and the breadth of the claims which fails to provide particular steps involved in the prevention diabetes, stroke, colitis, atherosclerosis, sepsis, stroke or myocardial infarction, the specification fails to teach the skilled artisan in the art how to make and use the 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Majerus et al. (JBC, 2003 – cited herein).
Majerus et al. teach:
Regarding claims 1-2, a human ADAMTS13 which has the furin protease cleavage site RQRR74 replaced with KQDR74, resulting in a furin protease resistant ADAMTS13 protein which retains VFW-cleaving activity – See Abstract, p. 5 (Furin Consensus Site Is Required….); and p. 6 (Secreted Pro-ADAMTS13 is Proteolytically Active).
Regarding claim 4, furin is involved in coagulation given the fact it processes/cleaves Factor VIII and Factor X as evidenced by MedChemExpress Furin product information.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 27 August 2026
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