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 .
Election/Restrictions
Applicant’s election without traverse of Group I, in the reply filed on 8/23/25 is acknowledged. Election was made without traverse of SEQ ID NO: 5 (Boskar-4) which is a single chain polypeptide.
Please note that SEQ ID NO: 5 was found free of the art, therefore the search was extended to the unelected species.
Claims 99, 101 and 105 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 1-3, 9, 13,16,18, 22, 24-25, 36, 47, 58,69, 80-81,99, 101 and 105 are pending.
Claims 1-3, 9, 13, 16, 18, 22, 24-25, 36, 47, 58 , 69, 80 and 81 read on Group I and are under consideration.
Claim Objections
Claim 1 is objected to because of the following informalities: G-CSF should be completely spelled out the first time it appears followed by the acronym in parenthesis.
Claim 3 is objected to because of the following informalities: HSPCs should be completely spelled out the first time it appears followed by the acronym in parenthesis.
Claim 3 is objected to because of the following informalities: “deriving thereof” should be amended to “derived therefrom”.
Claim 9 is objected to because of the following informalities: “wherein the protein comprises no disulfide bonds” is duplicated.
Appropriate correction is required.
Claim Interpretation
Claim 1 is drawn to:
a protein comprising:
One or two polypeptide chains
A bundle of four α-helices; and
Two or three amino acid linkers that connect contiguous bundle forming α-helices that are located on the same polypeptide chain, wherein each amino acid linker has a length between 2 and 15 amino acids;
Wherein the protein comprises one or more G-CSF receptor binding sites and wherein the protein has a melting temperature of at least 74C.
Claim 1 is interpreted to require one or two polypeptide chains, a bundle of four α-helices and two or three amino acid linkers that connect the bundle forming α-helices, wherein the linker is limited to 2 to 15 amino acids. The protein also must comprise one or more G-CSF receptor binding site and have a Tm of at least 74C.
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 1-3, 9, 13, 16, 18, 22, 24-25, 36, 47, 58, 69, 80 and 81 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Scope of the claimed genus
Claim 1 is drawn to:
a protein comprising:
One or two polypeptide chains
A bundle of four α-helices; and
Two or three amino acid linkers that connect contiguous bundle forming α-helices that are located on the same polypeptide chain, wherein each amino acid linker has a length between 2 and 15 amino acids;
Wherein the protein comprises one or more G-CSF receptor binding sites and wherein the protein has a melting temperature of at least 74C.
Claim 2 is drawn to wherein the G-CSF-receptor binding site individually comprises 6 to 8 residues having a similar structure and similar spatial orientation toward each other as the amino acids… Claim 3 is drawn the protein of claim 1 that binds to G-CSF-R with an affinity of less than 10µm, has G-CSF-like activity and the activities of 1-iv. Claim 13 claims the polypeptide chain comprises an amino acid sequence having at least 60% identity with SEQ ID NO: 5, 4, 3 , 2, 6, 14, 22 and 25. Claim 22 claims wherein both polypeptide chains comprise an amino acid sequence having at least 60% to SEQ ID NO: 19, 18, 32 and 33. Claim 24 is drawn to the spatial orientation and molecular feature of human G-CSF (claim 1). The USPTO provides claim terms with broadest reasonable interpretation in light of the specification. The instant specification defines “G-CSF-like activity” as [PGPUB0151]:
“G-CSF-like activity” may refer to any activity of a protein that results in a similar response as the binding of G-CSF to the extracellular ligand-binding domain of G-CSF-R.”. However, this is not a clear definition since it unclear what is similar activity.
Assessment of whether species are support in the original specification
SEQ ID NO: 5, 6 and 19 were the only proteins disclosed as having a Tm of greater than 74C (Table 6). It is important to note that human wild-type G-CSF has a Tm of 57C. Therefore, SEQ ID NO: 5, 6 and 19 have a significant increase in Tm compared to the control. Applicants disclosed experiments with SEQ ID NO: 4, 5, 14, 6 and 19 (proliferation of NFS-60 cells, granulocytic differentiation of HSPCs, induction of CFUs in HSPCs). In addition, the complete structure of the following species was disclosed: SEQ ID NOs: 2-33.
There were no other sequences described other than SEQ ID NO: 5, 6 and 19 that meet the limitations of claim 1 and have a Tm of at least 74C. There was no disclosure of other peptide sequences that had at least 60% sequence identity to thereto and had the claimed activities and Tm.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of 5, 6 and 19 at the time the invention was filed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the disclosure of the sequences are not representative of the genus. The disclosure of the sequences are not representative of the entire genus encompassed by claim 1 is enormous.
With the aid of a computer, one of ordinary skill in the art could identify all of the peptides with at least 60% homology to SEQ ID Nos: 5, 4, 3, 2, 6, 14, 22, 25, 19, 18, 32, 33. However, there is no teaching regarding which 40% of the amino acids can vary from the sequences and still result in a protein that has the claimed Tm and claimed properties. For example, SEQ ID NO: 5 is 123 amino acids in length and can have 49 amino acid substitutions, deletions and/or additions and still meet the structural requirements of the claims. If one considers that there are 20 natural amino acids and a great number of non-natural amino acids and the substitutions/deletions/additions can occur at any position of the peptide, the number of peptides that meet the requirement of 60% sequence identity is enormous.
Therefore, disclosure of SEQ ID NO: 4, 5,14, 6 and 19 are not representative of the genus.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of a protein that has the claimed activity.
The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus. Wild type human G-CSF has a Tm of 57C. The specification does not describe the physical basis for increasing the Tm. Furthermore, there is a large difference in activity between the sequences. For example, Table 5 discloses an EC50 (NFS-60) of 3225 ng/ml for SEQ ID NO: 3 and 27 ng/ml for SEQ ID NO: 5. The instant claims also do not clearly define the C-GSF receptor binding site. Claim 2 recites that the G-CSF receptor binding site comprises 6 to 8 amino acids that have similar structure and similar spatial orientation. This does not clearly describe the structure necessary for the claimed function. The instant specification does not describe the structure necessary for increase in Tm and the functions of claims 3
This is an issue of written description. The specification does not make clear which proteins are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which proteins to make.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of SEQ ID NO: 5, 6 and 19.
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 1-3, 9, 13, 16, 18, 22, 24-25, 36, 47, 58, 69, 80 and 81 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.
Claim 1 is indefinite because the limitation “..that connect contiguous bundle forming α-helices”. It is unclear whether the bundle forming α-helices referenced in part c are the same four alpha helices recited in part b or whether they refer to a different subset of α-helices. The claim does not provide explicit antecedent basis for the “bundle forming α-helices”. Therefore, a person of ordinary skill in the art would not be able to determine which α-helices are connected by the recited linkers.
Claims 2-3, 9, 13, 16, 18, 22, 24-25, 36, 47, 58, 69, 80 and 81 are rejected for depending from rejected claim 1.
Claim 2 is indefinite because the term “similar” is a relative term which renders the claim indefinite. The limitation “similar structure and similar spatial orientation” 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. Furthermore, the claim is indefinite because it relies on human G-CSF as a reference structure even though claim 1 does not recite human G-CSF. As written it is unclear how the protein of claim 1 is to be compared to human G-CSF.
Claim 3 is indefinite because the term “has G-CSF-like” activity is a relative term which renders the claim indefinite. The limitation “G-CSF-like” activity 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. The instant specification states “G-CSF-like activity” may refer to any activity of a protein that results in a similar response as the binding of G-CSF to the extracellular ligand-binding domain of G-CSF-R.”. However, this is not a clear definition since it unclear what is similar activity.
Regarding claim 3, 13, 16, 18, 22, 36, 47, 58, 69, 81 the phrase "in particular" in the context of the claims is interpreted as “for example” or “such as” and renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 3, 58, 69 the phrase "preferably", “more preferably”, “most preferably”, and “even more preferably” in the context of the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 9 recites the limitation "the calculated contact order number" in line two. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite a calculated contact number.
Claim 18 is indefinite because claim 1 requires contiguous bundle forming α-helices located on the same polypeptide chain and connected by the recited linkers, whereas claim 18 recites a four helical bundle formed by two different peptide chains. It is unclear which α-helices are connected by the recited linkers, how the “contiguous” requirement is satisfied in the two polypeptide chain embodiment and whether the linker limitation (in claim 1) is compatible with the structural arrangement recited in claim 18.
Claim 24 is indefinite because it relies on human G-CSF as a reference structure even though claim 1 does not recite human G-CSF. As written it is unclear how the protein of claim 1 is to be compared to human G-CSF.
Claim Rejections - 35 USC § 103
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 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.
Claims 1-3, 9, 13, 24 and 80-81 are rejected under 35 U.S.C. 103 as being unpatentable over Carter (WO2006128176, cited on IDS) as evidenced by Hill et al. (Proc. Natl. Acad. Sci USA Vol 90, pp 5167-5171, June 1993).
Carter teach G-CSF fusion proteins that retain G-CSF function (Abstract). Carter teaches that G-CSF may be modified in the external loop regions by deletions [0066].
Carter teaches preferred loops for such alterations are the AB loop and the CD loop. One may prepare an abbreviated G-CSF molecule by deleting a portion of the amino acid residues found in the external loops said abbreviated G-CSF molecule may have additional advantages in preparation or in biological function [0066]. Carter teaches the domains at residues 11-57 and 100-118 are required for receptor binding [0075].
As evidenced by Hill et al., the AB loop is 31 amino acids and the CD loop is 19 amino acids, the BC loop is 8 amino acids (Fig. 2). Please note that the loop region amino acid length is calculated by the amino acids between helices A, B, C and D. Therefore, the structure of G-CSF is a single polypeptide chain, with a bundle of 4 α-helices and three linkers (loop regions) that connect contiguous bundle forming α-helices. Only one of the loops is between 2 and 15 amino acids (please see Fig. 2 of Hill et al.). G-CSF protein comprises at least one G-CSF binding sites. Please not that MPEP 2131.01 states: that an extra reference or evidence can be used to show an inherent characteristic of the thing taught by the primary reference.
It would have been obvious to a person of ordinary skill in the art to optimize the loop region (linkers) AB and CD by deletion of amino acids to arrive at a loop region between 2-15 amino acids. A person of ordinary skill in the art would have a motivation because Carter teaches deleting a portion of the amino acid residues found in the external loops may have additional advantages in preparation or in biological function. There is a reasonable expectation of success given that methods of making deletions to polypeptides are well known in the art.
With respect to the limitation “has a Tm of at least 74C) (claim 1)” and the limitations of claim 3, the G-CSF made obvious by Carter would inherently have all of the activities and properties of the composition of claims 1 and 3. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, Carter makes obvious the same composition therefore the same composition would have the same properties. Moreover, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
With respect to claims 2 and 24, Carter teaches the G-CSF receptor binding sites are residues 11-57 and 100-118 and teaches the receptor binding domain remain intact.
With respect to claim 9, Carter teaches host cells for the preparation of G-CSF with the prevention of sugar groups (glycosylation) [0055].
With respect to claim 13, as evidenced by Hill et al. the α-helices that form the bundle are located on a single peptide chain (Fig. 2).
With respect to claims 80 and 81, Carter et al. teach a composite molecule having two portions, a first portion comprising a recombinant molecule with G-CSF activity and a second portion with a molecule with G-CSF activity, a molecule with a reproductive system function, a molecule with cytokine function or targeting function (claim 1). Carter teaches a molecule with G-CSF function can represent native G-CSF or derivatives comprising additions or deletions, meeting the limitation of first and second domain. Carter teaches and claims a linker between the first and second portion (claim 6 [0081]). Carter teaches another source of modified G-CSF molecule that can be used in a composite of interest is one with an additional one more amino acids added to one or both of the termini. Such additional amino acids can be added practicing known methods, such as subcloning an appropriate polynucleotide upstream or downstream of the open reading frame. Alternatively, an oligopeptide can be ligated to either or both termini [0069].
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654