DETAILED ACTION
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 . 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 30 Dec, 2025 has been entered.
Election/Restrictions
Applicants elected group I (polypeptides) and SEQ ID 9 without traverse in the reply filed on 13 May, 2024.
Claims Status
Claims 1, 4-13 and 15-21 are pending.
Claims 1 and 4 have been amended.
Claims 20 and 21 are new.
Claims 5-10 and 15-18 have been withdrawn due to an election/restriction requirement.
Maintained/Modified Rejections
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
first rejection
Claim(s) 1, 2, 4, 11-13, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Ko (KR 20170138920, cited by applicants) in view of Kratz (J. Control. Rel. (2008) 132 p171-183) and Li (CN 104119448, cited by applicants).
Note that Ko is in Korean. US 20190133173, in the same patent family, is used as a translation; all references to locations in the reference are to the US PGPub document. In addition, Li is in Chinese. A machine translation is relied upon for this reference, and all references to locations in the reference are to the machine translation unless otherwise noted.
Ko discusses the slit-robo system for treating sarcopenia (title). An LRRD2 fragment is sufficient to treat the disorder, the whole Slit protein is not required (paragraph 11), which can be SEQ ID 4 (paragraph 24), which is a fragment of SEQ ID 3 of the instant claims (32 AA removed from the N-terminus and 49 removed from the C-terminus). This sequence is explicitly mentioned as a therapy (paragraph 30), and examples show the effectiveness of the LRRD2 domain without the rest of the Slit3 sequence (paragraph 98). Formulations can be parenteral, including saline or other buffer (paragraph 115) and can be injected (paragraph 119).
The difference between this reference and the examined claims is that this reference does not discuss conjugation to albumin.
Kratz discusses albumin as a drug carrier (title), which can improve the pharmacokinetics of protein drugs (p171, 1st column, 1st paragraph). Rapid kidney clearance and stability can be improved by albumin binding (p173, 2nd column, 1st and 2nd paragraphs), and albumin has an average half life of 19 days (p171, 1st column, 1st paragraph). This can be done by genetic manipulation, where the gene for albumin is fused to the gene for the drug (p173, 2nd column, 3d paragraph). An example using human serum albumin fused to the N-terminus of interferon was given (fig 9, p179, 2nd column, top of page, p179, 1st column, 7th paragraph). This reference discusses attachment of albumin to increase the plasma lifetime, and other beneficial effects.
Li discusses the LRR sequence of the Slit proteins (paragraph 7), which is clearly the same Slit protein as applicants. A preferred sequence is SEQ ID 5 (paragraph 42), which is identical to SEQ ID 3 of the examined claims, save that it has 14 additional amino acids on the C-terminus (p15-16 of the original document). This reference shows that the LRRD2 sequence of Ko is not the universally accepted extent of the domain.
Therefore, it would be obvious to attach a human albumin to the sequence of Ko, as Kratz teaches that this will improve the pharmacokinetics of the drug. As Kratz is a generic reference, discussing many different drugs (including protein drugs) that can be attached to albumin, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use the LRRD2 domain of Li instead of the LRRD2 domain of Ko, as a simple substitution of one known element for another yielding expected results. As the sequence of Li includes the sequence of Ko, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Alternatively, as Ko shows that the shorter domain is active, a person of skill in the art would recognize that the sequence of Li is also active, even if 1, 10, or 20 amino acids are removed from the C-terminus – or 14. Thus, these sequences are equivalent. Or that the range of the number of amino acids added to the C-terminus of the sequence of Ko can be extended to the limit shown by Li – a range does not have to have both endpoints given by the same reference (MPEP 2144.05(I))
Ko discusses a Slit3 LRRD2 protein for treatment of sarcopenia. Kratz renders obvious attachment to albumin, The sequence of Li comprises SEQ ID 3, rendering claim 4 obvious. Alternatively, Ko and Li show a range of extension that is possible from the peptide of Ko, which includes a sequence consisting of SEQ ID 3, rendering it obvious.
Kratz gives an example of human albumin attached to the N-terminus of a protein, rendering obvious claims 1, 3, and 4.
Ko discusses pharmaceutical compositions, rendering obvious claim 11.
Ko discusses injections, so the formulation must be suitable for that purpose, rendering obvious claim 12.
Ko states that the drug can be used to treat sarcopenia, rendering obvious claim 13.
Krats states that attachment to albumin will improve pharmacokinetics, with a 19 day half life, which renders obvious claim 20.
The construct has every parameter that applicants state is important for binding, so it will necessarily meet the limitations of claim 21
response to applicant’s arguments
Applicants argue that the LRRD2 domain is difficult to fold, is poorly soluble, and has high structural instability, so that a person of skill in the art would assume a fusion protein would disrupt the domains structure, that the placement of the albumin is non-obvious, and that the sequence is the minimum essential length. This is supported by a declaration by Dr. Jung-Min Koh, applicant.
Applicant's arguments filed 30 Dec, 2025 have been fully considered but they are not persuasive.
Applicants argue that the LRRD2 domain is difficult to fold, poorly soluble, and has high structural instability, so a fusion protein would be expected to fail. The evidence of this is two references discussing insoluble LRR domains when produced in E-coli. However, this is a well known and very common problem with recombinant production (Mital et al, Mcrob. Cell. Fact. (2021) 20:208 abstract), and has nothing to do with the LRR sequence. The prior art on LRR sequences contradicts applicant’s arguments. Park et al (Nat. Struct. Mol. Biol. (2015)) states that leucine rich repeats and other repeat protein scaffolds have high stability (1st page, 1st column, 1st paragraph). Bella et al (Cell. Mol. Life Sci. (2008) 65 p2307-2333) discusses a library of LRR sequences, which are described as highly soluble proteins (p2328, 1st column, 3d paragraph). In other words, applicant’s evidence does not prove what they are arguing, and the prior art directly contradicts their arguments. Note that one of the references that applicants are pointing to (Hong et al) solved the production problem by making a fusion protein; the exact thing that applicants are arguing would be expected to fail.
Applicants are arguing that fusing the albumin to the N-terminus is better than fusing to the C-terminus, which they claim is unexpected. It is not clear why. It is known that the fusion can interfere with biological activity (Francis et al , Curr. Prot. Protein Sci. (2010) 5.24-1-5.24.29, 11th page, 1st column, 2nd paragraph), and that this can be changed by placing it on the other terminus (Christensen et al, Prot. Sci. (2009) 18 p1377-1387, abstract). In other words, applicants are describing routine optimization.
Finally, applicants argue that the claimed sequence is the minimum essential length. This is not correct; Ko clearly shows a shorter sequence with activity.
second rejection
Claim(s) 1, 4, 11-13, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ko (KR 20170138920, cited by applicants) in view of Kratz (J. Control. Rel. (2008) 132 p171-183), Li (CN 104119448, cited by applicants), Baumhof et al (US 20180312545) and Kimple et al (Curr. Protoc. Protein Sci. (2015) 73).
As noted above, Ko, Kratz, and Li render obvious claims 1, 4, 11-13, 20, and 21.
The difference between these references and the remaining claims is that these references do not discuss a signal sequence or a FLAG tag.
Baumhof et al discuss optimizing nucleic acid molecules (title). Signal peptides can promote or improve the secretion of a target protein (paragraph 170). These are usually placed on the N-terminus (paragraph 166), and include SEQ ID 273 (paragraph 170), which is identical to SEQ ID 1 of the examined claims. This reference discusses the advantages of signal peptide sequences.
Kimple et al discuss affinity tags (title). Short epitope tags such as FLAG rarely affect the properties of the proteins they are bound to, can be used to detect the proteins in vitro and in cell culture, and are very specific for their respective antibodies (7th page, 4th paragraph). These can be used for purification, with release by pH modification, EDTA, or competition with FLAG peptide (table 9.9.1, 19th page). This reference discusses the use of the FLAG sequence.
Therefore, it would be obvious to add a signal sequence, such as SEQ ID 273 of Baumhof et al, to the N-terminus of the construct of Ko, Kratz, and Li, to promote and improve the secretion of the construct during recombinant synthesis, as discussed by Baumhof et al. As this Baumhof et al is agnostic as to the target protein, an artisan in this field would attempt this addition with a reasonable expectation of success.
Furthermore, it would be obvious to add a FLAG tag to the construct, to allow detection of the construct in vitro and in cell culture, and to allow purification of the material afterwards, as described by Kimple et al. As this sequence is commonly used for this purpose, an artisan in this field would attempt this process with a reasonable expectation of success.
response to applicant’s arguments
Applicants have used the same arguments for both rejections under this statute, which were discussed above.
New Rejections
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.
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 20 and 21 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.
Claim 20 states that the construct have a half life in blood at least 14 fold higher than without the albumin. This includes 20 fold higher lifetime, for example. But the support for this amendment is a statement that the sequence has about a 14 fold higher half life, which does not provide support for longer half lifes.
Claim 21 requires the construct have higher binding affinity than two other constructs. Applicants point to some graphs which “illustrate the receptor binding ability of the various forms of HAS-Slit3 LRRD2 fusion proteins (p5, line 7 and 8). However, nowhere do applicants show what the binding affinity of these constructs are, much less show that they are at least 2x higher. Even if they did, similar to claim 20, that would be an exact ratio, not any ratio above a certain level.
In addition, the construct is the fusion protein of claim 1. Applicants have data for an embodiment of the proteins of claim 1, but not for every embodiment of the claims, nor have they provided any extrapolation to the entirety of the claim in their discussion. Thus, these claims comprise new matter.
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.
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.
first rejection
Claim 20 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.
Claim 20 requires that the blood half life be at least 14x higher than a construct without albumin. However, the test is not defined. If, for example, the test subject has an immune response to human albumin, this limitation would not be met, even if the same construct would meet the limitation in a human patient.
second rejection
Claim 21 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.
Claim 21 requires binding affinity that is greater than other proteins. However, binding affinity to what is not defined. The only binding in the claims is to albumin, and that is via a protein fusion.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
