DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Responses to Election/Restriction filed on 4/24/2026 and 7/2/2026 are acknowledged.
3. Claim filed on 7/2/2026 is acknowledged.
4. Claims 2-32, 34-68, 72, 83-87 and 92-118 have been cancelled.
5. New claim 119 has been added.
6. Claims 1, 33, 69-71, 73-82, 88-91 and 119 are pending in this application.
7. Claims 80-82 and 89-91 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim.
8. Claims 1, 33, 69-71, 73-79 and 119 are under examination.
Elections/Restrictions
9. Applicant’s election without traverse of Group 1 (claims 1, 33, 69-71, 73-79 and 119) and election without traverse of a modified DLK1 ECD consisting of SEQ ID NO: 2 having a deletion of Gly199 as species of modified DLK1 extracellular domain (ECD); and a single chain protein consisting of, from N-terminal to C-terminal, an IgK signal peptide, the sequence of SEQ ID NO: 1 having a deletion of Gly199 and a polyhistidine tag as species of single chain protein in the replies filed on 4/24/2026 and 7/2/2026 are acknowledged. The requirement is made FINAL in this office action.
Group 1 is drawn to a modified DLK1 extracellular domain (ECD), the DLK1 ECD domain having the sequence of SEQ ID NO: 2, wherein the modification is a substitution or deletion of Gly199; a substitution or deletion of Arg267; a substitution or deletion of Val272; a substitution or deletion of Arg160 and Gly199; a substitution or deletion of Arg160 and Arg267; a substitution or deletion of Arg160 and Val272; a substitution or deletion of Gly199 and Arg267; a substitution or deletion of Glyl99 and Val272; a substitution or deletion of Arg267 and Val272; a substitution or deletion of Glu377; a substitution or deletion of Ala378; a substitution or deletion of Gly379; a substitution or deletion of Asp380; a substitution or deletion of Glu381; a substitution or deletion of Glu382; a substitution or deletion of Ile383; a substitution or deletion of residues 377-383; a substitution or deletion of 2 of residues 377-383; a substitution or deletion of 3 of residues 377-383; a substitution or deletion of 4 of residues 377-383; a substitution or deletion of 5 of residues 377-383; a substitution or deletion of Ala171; a substitution or deletion of Ser173; a substitution or deletion of Cys174; a substitution or deletion of Thr186; a substitution or deletion of Asp187; a substitution or deletion of two of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of three of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of four of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution, deletion, insertion, or modification of Cys174; a substitution, deletion, insertion, or modification of Cys179; a substitution, deletion, insertion, or modification of Cys185; a substitution, deletion, insertion, or modification of Cys194; a substitution, deletion, insertion, or modification of Cys196; a substitution, deletion, insertion, or modification of Cys205; a substitution, deletion, insertion, or modification of Cys212; a substitution, deletion, insertion, or modification of Cys217; a substitution, deletion, insertion, or modification of Cys223; a substitution, deletion, insertion, or modification of Cys233; a substitution, deletion, insertion, or modification of Cys235; or a substitution, deletion, insertion, or modification of Cys244; a single chain protein comprising such modified DLK1 ECD; and a full length DLK1 protein comprising such modified DLK1 ECD. A search was conducted on the elected species; and these appear to be free of prior art. A search was extended to the genus in claims 1, 69 and 119; and the modified DLK1 ECD with the modifications recited in claim 1 that can be searched and examined, a single chain protein comprising such modified DLK1 ECD and a full length DLK1 protein comprising such modified DLK1 ECD appear to be free of prior art. Claims 1, 33, 69-71, 73-79 and 119 are examined on the merits in this office action.
Claim Interpretations
10. With regards to the modified DLK1 ECD recited in instant claim 1, since instant claim 1 recites the term “wherein the modification is…”, the Examiner is interpretating the modification in the modified DLK1 ECD recited in instant claim 1 is limited to those recited in instant claim 1. Such interpretation applies to all rejections set forth below.
Objections
11. The specification is objected to for the following minor informality: The specification recites “(https://github.com/broadinstitute/inferCNV)” on page 32, paragraph [0117] of instant specification. The embedded hyperlinks and/or other forms of browser-executable code are impermissible and require deletion. It is suggested that Applicant places a URL between these symbols “< >” to inactivate the hyperlinks. Applicant is required to correct these errors.
Please note: The specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification (see MPEP § 608.01).
12. The drawings are objected to for the following minor informality:
Each of Figures 2 A and 2B needs its individual description of the drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
13. Claim 1 is objected to for the following minor informality: Claim 1 contains the acronym “DLK1”. An acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, for example, delta-like non-canonical notch ligand 1 (DLK1). The abbreviation can be used thereafter.
Furthermore, Applicant is suggested to amend claim 1 as “A modified delta-like non-canonical notch ligand 1 (DLK1) extracellular domain (ECD), wherein the DLK1 ECD domain consists of SEQ ID NO: 2, and wherein the modification is…”.
In addition, claim 1 recites “a substitution or deletion of Cys174” and “a substitution, deletion, insertion, or modification of Cys174”. Applicant is required to amend claim 1 to recite only one type of modification of Cys174.
14. Claim 33 is objected to for the following minor informality: Applicant is suggested to amend claim 33 as “The modified DLK1 ECD of claim 1, wherein the modified DLK1 ECD comprises a modified signal peptide, and wherein at least one amino acid of the signal peptide of DLK1 ECD is substituted or deleted”.
15. Claim 71 is objected to for the following minor informality: Claim 71 contains the acronym “IgK”. An acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, for example, immunoglobulin K (IgK). The abbreviation can be used thereafter.
Furthermore, Applicant is suggested to amend claim 71 as “…wherein the signal peptide is an…”.
16. Claim 73 is objected to for the following minor informality: Claim 73 contains the acronym “EGF”. An acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, for example, epidermal growth factor like (EGF). The abbreviation can be used thereafter.
17. Claim 78 is objected to for the following minor informality: Claim 73 contains the acronym “ADAM17/TNFα”. An acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, for example, a disintegrin and metalloproteinase 17 (ADAM17)/tumor necrosis factor-alpha (TNFα). The abbreviation can be used thereafter.
Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
18. 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.
19. Claims 1, 33, 69-71, 73-79 and 119 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 pre-AIA the applicant regards as the invention.
20. Claim 1 recites “A modified DLK1 extracellular domain (ECD), the DLK1 ECD domain having the sequence of SEQ ID NO: 2, wherein the modification is a substitution or deletion of Gly199; a substitution or deletion of Arg267; a substitution or deletion of Val272; a substitution or deletion of Arg160 and Gly199; a substitution or deletion of Arg160 and Arg267; a substitution or deletion of Arg160 and Val272; a substitution or deletion of Gly199 and Arg267; a substitution or deletion of Glyl99 and Val272; a substitution or deletion of Arg267 and Val272; a substitution or deletion of Glu377; a substitution or deletion of Ala378; a substitution or deletion of Gly379; a substitution or deletion of Asp380; a substitution or deletion of Glu381; a substitution or deletion of Glu382; a substitution or deletion of Ile383; a substitution or deletion of residues 377-383; a substitution or deletion of 2 of residues 377-383; a substitution or deletion of 3 of residues 377-383; a substitution or deletion of 4 of residues 377-383; a substitution or deletion of 5 of residues 377-383; a substitution or deletion of Ala171; a substitution or deletion of Ser173; a substitution or deletion of Cys174; a substitution or deletion of Thr186; a substitution or deletion of Asp187; a substitution or deletion of two of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of three of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of four of residues Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution or deletion of Ala171, Ser173, Cys174, Thr186, and Asp187; a substitution, deletion, insertion, or modification of Cys174; a substitution, deletion, insertion, or modification of Cys179; a substitution, deletion, insertion, or modification of Cys185; a substitution, deletion, insertion, or modification of Cys194; a substitution, deletion, insertion, or modification of Cys196; a substitution, deletion, insertion, or modification of Cys205; a substitution, deletion, insertion, or modification of Cys212; a substitution, deletion, insertion, or modification of Cys217; a substitution, deletion, insertion, or modification of Cys223; a substitution, deletion, insertion, or modification of Cys233; a substitution, deletion, insertion, or modification of Cys235; or a substitution, deletion, insertion, or modification of Cys244”. First, the DLK1 ECD consisting of the amino acid sequence of instant SEQ ID NO: 2 is 304 amino acids in length and has Pro at position 160. Therefore, it is unclear what the modifications of the amino acid at any position above 304 are; and to what the recited “Arg160” is referring. Second, with regards to the recited insertions of various Cys residues, such as insertion of Cys174 and many others, it is unclear what the recited insertions of various Cys residues are. Taken all these together, the metes and bounds of instant claim 1 is vague and indefinite. Because claims 33, 69-71, 73-79 and 119 depend from and/or recite the limitations of indefinite claim 1, and none of the dependent claims clarifies the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Furthermore, in the instant case, it is impossible for the Examiner to search and/or examine such modifications listed above. Therefore, such modifications would not be searched and examined in the current office action.
21. Claim 70 recites “The single chain protein of claim 69, further comprising a signal peptide”; and claim 69 recites “A single chain protein comprising a modified DLK1 ECD of claim 1”. According to instant specification, DLK1 of instant SEQ ID NO: 1 is 383 amino acids in length; the DLK1 ECD of instant SEQ ID NO: 2 is amino acids 1-304 of the DLK1 of instant SEQ ID NO: 1; and the amino acids 1-23 of instant SEQ ID NO: 1 or 2 is a single peptide (see page 2, paragraphs [0007] and [0010] of instant specification). Therefore, in the instant case, it is unclear whether the recited “a signal peptide” in instant claim 70 is limited to a single peptide that is not presented in the DLK1 ECD or not. Thus, the metes and bounds of instant claim 70 is vague and indefinite.
Furthermore, for the purpose of this examination, the Examiner is interpretating the recited “a signal peptide” in instant claim 70 is different from the one presented in the modified DLK1 ECD recited in instant claim 1. Therefore, claim 70 would not be rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph.
Claim Rejections - 35 U.S.C. § 112 paragraph (d)
22. 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 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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.
23. Claims 33 and 73-77 are rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 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. 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.
24. Claim 33 depends on claim 1; and claim 33 recites “The modified DLK1 ECD of claim 1, having a modified signal peptide comprising: a substitution or deletion of 1 residue of the signal peptide, 2 residues of the signal peptide, 3 residues of the signal peptide, 4 residues of the signal peptide, 5 residues of the signal peptide, 6 residues of the signal peptide, 7 residues of the signal peptide, 8 residues of the signal peptide, 9 residues of the signal peptide, 10 residues of the signal peptide, 11 residues of the signal peptide, 12 residues of the signal peptide, 13 residues of the signal peptide, 14 residues of the signal peptide, 15 residues of the signal peptide, 16 residues of the signal peptide, 17 residues of the signal peptide, 18 residues of the signal peptide, 19 residues of the signal peptide, 20 residues of the signal peptide, 21 residues of the signal peptide, 22 residues of the signal peptide, or 23 residues of the signal peptide”. However, in the instant case, as stated in Section 10 above, since instant claim 1 recites the term “wherein the modification is…”, the Examiner is interpretating the modification in the modified DLK1 ECD recited in instant claim 1 is limited to those recited in instant claim 1. Therefore, the scope of the modified DLK1 ECD recited in instant claim 33 is broader than the scope of the modified DLK1 ECD recited in claim 1. Claim 33 does not further limit the modified DLK1 ECD of claim 1; thus, claim 33 is improper dependent forms for failing to further limit the subject matter of claim 1.
25. Claims 73-77 depend on claim 69; and claim 69 recites “A single chain protein comprising a modified DLK1 ECD of claim 1”. And as stated in Section 10 above, since instant claim 1 recites the term “wherein the modification is…”, the Examiner is interpretating the modification in the modified DLK1 ECD recited in instant claim 1 is limited to those recited in instant claim 1. Furthermore, according to instant specification, the DLK1 ECD of instant SEQ ID NO: 2 comprises six epidermal growth factor like (EGF) domains (referred to as EGF1, EGF2, EGF3, EGF4, EGF5, and EGF6) (see page 6, paragraph [0035] of instant specification). Therefore, the scope of the modified DLK1 ECD recited in instant claims 73-77 is identical to the scope of the modified DLK1 ECD recited in claim 69. Claims 73-77 do not further limit the modified DLK1 ECD of claim 69; thus, claims 73-77 are improper dependent forms for failing to further limit the subject matter of claim 69.
Examiner’s Notes
26. The modified DLK1 ECD recited in claim 1 that is searchable, and the single chain protein and/or full length DLK1 protein comprising such searchable modified DLK1 ECD appear to be free of prior art. The closest prior art is Gomes et al (J Clin Endocrinol Metab, 2019, 104, pages 2112-2120). Gomes et al teach a modified human DLK1 protein comprises a Gly199Ala substitution and frameshift mutations, for example, page 2116, Figure 2 and Table 1. However, in the instant case, as stated in Section 10 above, since instant claim 1 recites the term “wherein the modification is…”, the Examiner is interpretating the modification in the modified DLK1 ECD recited in instant claim 1 is limited to those recited in instant claim 1. Therefore, the modified human DLK1 protein in Gomes et al comprises additional modifications that are not recited in instant claim 1. And there is no teaching, motivation, or other type of suggestion to modify the modified human DLK1 protein in Gomes et al and arrive at the modified DLK1 ECD recited in claim 1 that are searchable, and the single chain protein and/or full length DLK1 protein comprising such searchable modified DLK1 ECD. Thus, the modified DLK1 ECD recited in claim 1 that is searchable, and the single chain protein and/or full length DLK1 protein comprising such searchable modified DLK1 ECD are both novel and unobvious over the prior arts of record. And the modified DLK1 ECD recited in claim 1 that are searchable, and the single chain protein and/or full length DLK1 protein comprising such searchable modified DLK1 ECD are markedly different from what exist in nature.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LI N KOMATSU whose telephone number is (571)270-3534. The examiner can normally be reached Mon-Fri 8am-4pm EST.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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