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
The restriction election requirement was previously acknowledged. Claims 18-56 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/22/2024.
Amendments and Status of the Claims
This action is in response to papers filed 5th Nov 2025, in which claims 1, 5 – 6, and 10 - 11 were amended, no claims were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended:
claim 1 and claim 10 to overcome rejections of claims 1-17 under 35 USC § 112a, written description; the rejection of claims 1 – 2, 5 - 6, 8 – 9, and 11 - 17 has been overcome and is withdrawn but the rejection of claims 3 – 4, 7, and 10 has not been overcome and is maintained.
claim 1 with limitations from previous claims 3 and 5 to overcome rejections of claims 1-17 under 35 USC § 103; the rejection has not been overcome and is maintained.
Neither the amendments nor arguments are persuasive for the reasons discussed in this office action.
Arguments applicable to newly applied rejections to amended claims are addressed below. Arguments that are no longer relevant are not addressed.
Objections and Rejections not reiterated here are withdrawn. This Office Action makes new 112b and 112d rejections necessitated by amendment. This action is made FINAL.
Claims 1-17 are under consideration.
Drawings
The amended drawings were received on 5th Nov 2025. These drawings are acceptable.
Specification
The amendments to specification are entered.
Abstract
The abstract of the disclosure is objected to for reasons stated in the Non-final Office Action dated 8/11/2025 and reiterated below. Specifically, the abstract is not on a separate sheet of paper.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
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.
Claim 10 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. This is a new rejection necessitate by amendment.
Claim 10 recites the limitation "the" in “the substitutions” in line 3. There is insufficient antecedent basis for this limitation in the claim.
In the interest of compact prosecution, claim 10 will be interpreted as: The construct of claim 1, wherein the first and second nucleotide sequences of the construct comprise a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 3, wherein any changes to the sequence would result in only conservative amino acid substitutions when the nucleic acid sequence is translated to amino acids.
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 pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claims 2 - 7 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 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. This is a new rejection necessitated by amendment.
Regarding claim 2, claim 2 recites, wherein kallikrein-2 is human kallikrein-2. However, claim 1 upon which claim 2 depends, already recites human KLK2 (line 2). Therefore, claim 2 is not further limiting the subject matter of the claim upon which it depends.
Regarding claim 3, claim 3 recites, wherein the first nucleotide sequence encodes kallikrein-2 comprising the amino acid sequence of SEQ ID NO: 4 or a fragment thereof. However, claim 1 upon which claim 3 depends, requires kallikrein-2 comprise the amino acid sequence of SEQ ID NO: 4 (line 4). i.e., Claim 1 requires the nucleic acid sequence to encode ALL of SEQ ID NO: 4, whereas claim 3, as recited, allows the nucleic acid sequence to only encode a fragment of SEQ ID NO: 4. Therefore, not all the limitations of Claim 1 (comprising ALL of SEQ ID NO: 4) is included in claim 3. Therefore, claim 3 is rejected for failing to include all the limitations of the claim upon which it depends.
Regarding claim 4, claim 4 recites, wherein the first nucleotide sequence encodes kallikrein-2 comprising the nucleic acid sequence of SEQ ID NO: 1 or a fragment thereof. However, claim 1 upon which claim 4 depends, requires the nucleic acid that encodes kallikrein-2 comprise the amino acid sequence of SEQ ID NO: 4 (line 4). i.e., Claim 1 requires the nucleic acid sequence, SEQ ID NO 1, to encode SEQ ID NO: 4 which is 263 aa. SEQ ID NO 1 is 789 nucleotides. However, claim 4, as recited, allows the nucleic acid sequence to only encode a fragment of SEQ ID NO: 4, which is less than 263 aa. A nucleic acid that encodes a fragment of SEQ ID NO 1 is less than 789 nucleotides and therefore could not encode all of SEQ ID NO 4. Therefore, not all the limitations of Claim 1 (comprising ALL of SEQ ID NO: 4) is included in claim 4. Therefore, claim 4 is rejected for failing to include all the limitations of the claim upon which it depends.
Regarding claim 5, claim 5 recites, wherein the GPI attachment sequence comprises SEQ ID NO: 5. However, claim 1 upon which claim 5 depends, already recites a second nucleotide sequence encoding a glycosylphosphatidylinositol (GPI) attachment sequence comprising the amino acid sequence of SEQ ID NO: 5 (line 2). Therefore, claim 5 is not further limiting the subject matter of the claim upon which it depends.
Regarding claim 6, claim 6 recites, wherein the GPI attachment sequence is human placental alkaline phosphatase. However, claim 5 upon which claim 6 depends, recites the glycosylphosphatidylinositol (GPI) attachment sequence comprises of SEQ ID NO: 5 (line 2). SEQ ID NO: 5 is already human placental alkaline phosphatase. Therefore, claim 6 is not further limiting the subject matter of the claim upon which it depends.
Regarding claim 7, claim 7 recites, wherein the second nucleotide sequence encodes a GPI attachment sequence comprising the amino acid sequence of SEQ ID NO: 5 or a fragment thereof. However, claim 5 upon which claim 7 depends, requires GPI attachment sequence comprise SEQ ID NO: 5 (line 2). i.e., Claim 5 requires the amino acid sequence of the GPI attachment sequence to encode ALL of SEQ ID NO: 5, whereas claim 7, as recited, allows the nucleic acid sequence to only encode a fragment of SEQ ID NO: 5. Therefore, not all the limitations of Claim 5 (comprising ALL of SEQ ID NO: 5) is included in claim 7. Therefore, claim 7 is rejected for failing to include all the limitations of the claim upon which it depends.
Regarding claim 10, claim 10 recites, wherein the substitutions consist of conservative amino acid changes…(lines 3-4). However, claim 1 upon which claim 10 depends, recites … sequence comprise SEQ ID NO: 5 (line 6). i.e., Claim 1 requires the amino acid sequence of the GPI attachment sequence to encode ALL of SEQ ID NO: 5, whereas claim 10, as recited, allows the nucleic acid sequence to comprise amino acid substitutions stemming from SEQ ID NO: 5. Therefore, not all the limitations of Claim 1 (comprising ALL of SEQ ID NO: 5) is included in claim 10. Therefore, claim 10 is rejected 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.
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.
New Matter Rejection
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
Claim 10 is 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.
Regarding claim 10, the new limitation of wherein the substitutions consist of conservative amino acid changes that maintain GPI anchoring and surface expression activity, with respect to SEQ ID NO: 3 appears to represent new matter. No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation. For instance, the specification on pg. 8, Table 1: Exemplary GPI Attachment Sequences, lists several GPI attachment sequences. There are two examples of human placental alkaline phosphatase: SEQ ID NO: 9 and SEQ ID NO: 5. These two do not differ with respect to conservative substitutions as required by the claims, rather SEQ ID NO: 9 has an extra 9 amino acid residues in it. Such disclosure is not indicative of conservative substitutions with the proviso that GPI anchoring and surface expression activity of the corresponding translated protein are maintained, as required by the claim. Since no basis has been identified, claim 10 is rejected as incorporating new matter.
WRITTEN DESCRIPTION rejection.
Claims 3 – 4, 7, and 10 remain 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 for reasons stated in the Non-final Office Action dated 8/11/2025 and rewritten below to also address amendments. 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.
The independent claims are drawn to a recombinant nucleic acid construct encoding a kallikrein-2 fusion protein, said construct comprising: a first nucleotide sequence encoding kallikrein-2 (KLK2), and a second nucleotide sequence wherein said second nucleotide sequence encoding the GPI attachment sequence is positioned 3' to the first nucleotide sequence encoding kallikrein-2 and wherein the kallikrein-2 fusion protein is capable of being expressed on the surface of a cell as a membrane-anchored protein. Instant rejection is directed to dependent claims 3 – 4, 7, and 10 only. Claims 3 - 4 require the KLK2 sequence to be comprised by the sequence of SEQ ID NO: 4 or a fragment thereof and SEQ ID NO: 1 or a fragment thereof, respectively. Claim 7 requires the GPI attachment sequence to be comprised by the amino acid sequence of SEQ ID NO: 5 or a fragment thereof. Claim 10 requires the nucleotide sequence of the construct encoding KLK2 and GPI to be a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 3, wherein the substitutions consist of conservative amino acid changes that maintain GPI anchoring and surface expression activity. The latter wherein clause is being interpreted as: which may comprise changes such that when translated, only result in conservative substitutions with the proviso that GPI anchoring and surface expression activity of the corresponding translated protein are maintained. Thus, the claims identify the recombinant nucleic acid construct by function, where the function is to:
be expressed on the surface of a cell as a membrane-anchored protein.
The function of being expressed on the surface of the cell is met by the GPI attachment sequence.
Thus, one of skill in the art would recognize that it is the second nucleotide sequence, the GPI sequence, which is the critical sequence structure required to perform the claimed function of being expressed on the surface of a cell as a membrane-anchored protein. However, with respect to the GPI sequence, the claims recite … SEQ ID NO: 5 or a fragment thereof, but provide no structure of “the fragment thereof”, critical to performing the claimed function. With respect to the protein KLK2, dependent claims identify the recombinant nucleic acid construct by the structure of the first nucleotide sequence encoding kallikrein-2 (KLK2), as SEQ ID NO: 1 (claim 4), and the resultant amino acid sequence of KLK2 is SEQ ID NO: 4 (claim 3), The claims also do not limit the length of the first and second nucleotide sequences that must have at least 90% identity to SEQ ID NO: 3, as recited in claim 10, other than reciting wherein the substitutions consist of conservative amino acid changes that maintain GPI anchoring and surface expression activity. However, the latter is not discussed in the specification. One of skill in the art will not know how many or where such substitutions may be made.
Further, neither the claims nor the specification disclose what it means to be a fragment thereof with respect to KLK2 or with respect to function of maintaining the GPI anchoring and surface expression activity. Without any knowledge of what the core structure of KLK2 or the GPI moiety that maintains the GPI anchoring and surface expression activity, one of skill in the art would not know how to construct the recombinant nucleic acid encoding the KLK2 fusion protein.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials. Fiers v. Revel, 984 F.2d at 1171,25 USPQA2d, 1601; In re Smyth, 480 F.2d 1376,1383, 178 USPQ 279,284 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is an unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163.
Species Not Described
fragment thereof with respect to KLK2 (SEQ ID NO: 4 and 1, claims 3 – 4).
fragment thereof with respect to GPI (SEQ ID NO: 5, claim 7).
nucleotide sequence with at least 90% identity to SEQ ID NO: 3 wherein the substitutions consist of conservative amino acid changes that maintain GPI anchoring and surface expression activity. (claim 10).
SEQ ID NO: 3 is 891 nucleotides in length. A sequence having at least 90 % identity to SEQ ID NO: 3 includes a genus of sequences comprising nucleotide sequences that may be ≤10% different from SEQ ID NO: 3; i.e., 89 nucleotides could be different. Furthermore, a nucleotide sequence could be or have:
up to 10% of the nucleotides removed from SEQ ID NO: 3;
a single chunk comprising ≤10% of the nucleotides different from SEQ ID NO: 3;
every 10th nucleotide (starting at any position) different from SEQ ID NO: 3;
every 10th nucleotide (starting at any position) removed from SEQ ID NO: 3;
any other combination of nucleotides mutated or removed as long as the total adds up to ≤10% of total nucleotides.
Each of those categories comprises a broad subgenus with diverse members and different structures that affect their functions. Some of those structures may have altered regulatory activity or other altered function(s). The amendment, wherein the substitutions consist of conservative amino acid changes that maintain GPI anchoring and surface expression activity, limits the above changes to conservative substitutions. However, the specification does not discuss where the sequence corresponding to GPI within SEQ ID NO: 3 is, and within this portion of the sequence, which nucleotides may or may not affect GPI anchoring, so as to maintain GPI anchoring and surface expression activity.
Similar considerations can be made for the recitation of a fragment thereof.
Only specific sequences are described in the instant specification without any correlation to what core sequence is encompassed by the recited sequences. The breadth of the claimed genera is enormously broad with an unfathomable number of structurally divergent and diverse sequences. The Specification does not provide sufficient evidence that each member of the entire genus of sequences claimed would produce the intended function.
To provide adequate written description and evidence of possession of the claimed fusion protein genus, the instant specification can structurally describe representative fragments, and sequences that function in the fusion protein as claimed, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for fragments or sequences that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or amino acid/protein) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future fragments, or sequences yet to be discovered that may function as claimed.
In this case, the only factor present in the claims is a recitation of the first or second sequences function as discussed in the opening paragraph of the written description section. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose the structure of a fragment that functions as claimed, and only discloses exemplary fusion proteins. A definition by function does not suffice to define the genus because it is only an indication of what the fragments or sequences do, rather than what they are. The specification fails to provide the structural features coupled to the claimed functional characteristics, other than for the full-length KLK-2 bound to GPI by way of sequences claimed, not fragments of or similar sequences of the same. The instant specification fails to describe a representative number of fragments or sequences that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
Knowledge from the Art
Campbell (Chapter 5.5.1, Glycosylphosphatidylinositols, B. O. Fraser-Reid et al. (eds.), Glycoscience: Chemistry and Chemical Biology I-III, Vol 1, 2001) presents an overview on GPI structure and its use as anchor. Relevant Campbell recitation from pg. 1698, 2nd and 3rd paras:
“There is no apparent common feature of these proteins that would dictate their GPI-linked nature, and this is clearly demonstrated by the diversity of the proteins employing this mode of membrane attachment.”
And “Variations in GPI structure continue to be discovered at an alarming rate.”
Thus, the prior art has no showings of a core structure that must be maintained in a fragment of a GPI for GPI anchoring to be functional nor does it shed light on fragments of proteins that can or cannot be bound to a GPI anchor.
Conclusion of “Written Description
Given the lack of representative examples to support the full scope of the claimed fragments or sequences used to make the fusion protein, and lack of reasonable structure-function correlation with regards to the unknown sequences in the fusion protein or fragments that provide the claimed functions, and the inability of the art to resolve these issues, the present claims lack adequate written description.
Examiner Suggestion: Amend the claims to recite the sequence structure or recite publicly available or deposited constructs or cells comprising the constructs and/or delete the phrases a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence of and fragment thereof.
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 rejections below have been modified from Non-final Office Action dated 8/11/2025 in order to address limitations of dependent claims that have been introduced into independent claim 1.
Claim(s) 1 - 7, 9, 12 - 13, and 15 - 17 are rejected under 35 U.S.C. 103 as being unpatentable over Ring et al., (US 20180037898 A1) in view of Brittingham (CA 3148735 A1, published 4-2-2021, IDS cites the US PGPub), Brown (Brown, Abstract, Current Opinion in Immunology, Volume 5, Issue 3, 1993, Pages 349-354), Tindall et al., (US 5516639), and Bouquin (WO 2005073375) for reasons stated in the Non-final Office Action dated 8/11/2025 and reiterated below.
Regarding claims 1-3, 5, and 9, Ring taught recombinant nucleic acid construct encoding a polypeptide of interest (POI), said construct comprising: a nucleotide sequence comprising a POI, and a second nucleotide sequence encoding a glycosylphosphatidylinositol (GPI) attachment sequence, wherein said second nucleotide sequence encoding the GPI attachment sequence is positioned 3' to the first nucleotide sequence encoding the POI, and wherein the POI is capable of being expressed on the surface of a cell as a membrane-anchored protein (title, claims 1, 11, Fig. 1A). Ring define POI to be a polymer of amino acids, either natural or non-naturally occurring [0019]. Examples of POI could be: antibodies [0028], CV1 [0077], variants of PD-Ll that bind to T cell receptors [0145], variants of the cytokine receptor subunit IL2Rb [0149]. Thus, Ring’s invention allows for the addition of a GPI-anchor to any protein without undue experimentation. Ring taught that many GPI anchors were known in the art, including synthetic ones, and that GPI anchor signals have been successfully engineered onto the C-terminus of various proteins and are functional. See paragraphs [0060 – 0067]. Ring taught that proteins expressed on cell surfaces can be used for a diverse array of purposes.
Regarding claim 12, Ring taught that the nucleic acid encoding the fusion protein should be operatively linked to a suitable transcription initiation sequence (i.e. a promoter) and exemplified such constructs. See [0085 – 0094] and [0138] onwards.
Regarding claim 13, claim 13 requires that the construct comprise a mammalian promoter sequence 5’ to the first nucleotide sequence. Ring taught that the nucleic acid encoding the fusion protein should be operatively linked to a promoter where the promoter is functional in the host cell of interest (e.g., mammalian cell, last line of para [0080]).
Regarding claims 15 - 17, Ring taught that the nucleic acid encoding the fusion protein may be contained in any vector, so long as it is compatible with the host cell and exemplified such constructs. See [0098] and [0138] onwards.
Ring did not teach that the POI in the fusion protein is KLK2, or the sequences of a first nucleotide sequence of human KLK2 comprising the amino acid sequence of SEQ ID NO: 4 and a second nucleotide sequence encoding a glycosylphosphatidylinositol (GPI) attachment sequence comprising the amino acid sequence of SEQ ID NO: 5 (claim 1).
Brown taught GPI-anchored proteins activate T cells (title). Thus, GPI-anchoring results in expression of ligands on cell membranes that in turn activate T cells (see abstract). Brown did not teach a fusion of hKLK2 to a GPI attachment sequence, or a nucleic acid encoding such a fusion protein (claim 1).
Brittingham taught there was a need in the art for chimeric antigen receptors (CARs) that specifically target a human Kallikrein-2 (hK2), and disclosed such CARs and immunoresponsive cells, such as T-cells, comprising such CARs. See abstract, last sentence of Background, and claim 1. Brittingham used a recombinant hK2 (rhKLK2) as antigen to produce such CARs following previously published protocols (Example 10, pg. 181). The CAR-expressing T cells showed activity against VCap cells that naturally express hK2 on their cell surface but not DU145 cells that do not naturally express hK2 on their cell surface; i.e., activity was only seen in cells expressing the hKLK2 on the cell surface.
Neither Ring nor Brown or Brittingham taught sequences of hKLK2 and GPI attachment sequence; i.e., SEQ ID NO: 4 and 5, respectively (amendment to claim 1).
However, such sequences were known in the prior art in the references of Tindall and Bouquin, respectively.
Tindal taught a hKLK2 polypeptide sequence. Tindall taught that there was a need in the art for antibodies to human KLK2 (hK2), and disclosed such antibodies. See abstract, column 3, lines 20-21, and claim 4. Tindall raised the antibodies against peptides derived from the hKLK2 polypeptide sequence (column 10, lines 7-19, see also Table II at column 11). Tindal taught hKLK2 polypeptide sequence, disclosed as SEQ ID NO: 1, (hKLK2 amino acids 41-56: HCLKKNSQVWLGRHNL) was used to generate a protein for the production of antibodies (see e.g. column 3, lines 58-67 and column 4, lines 1-7 and Table II at column 11). This peptide is a fragment of instant SEQ ID NO: 4 (and 6). Tindall further contemplate other immunogenic hK2 subunits such as SEQ ID NOs: 2 – 10 (see e.g. column 4, lines 8-14). Tindall’s SEQ ID NO: 10 aligns with instant SEQ ID NO: 4 as shown below:
SEQ ID NO 10
LENGTH: 237
TYPE: PRT
Query Match 90.6%; Score 1315; Length 237;
Best Local Similarity 99.6%;
Matches 236; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 25 IVGGWECEKHSQPWQVAVYSHGWAHCGGVLVHPQWVLTAAHCLKKNSQVWLGRHNLFEPE 84
||||||||||||||||||:|||||||||||||||||||||||||||||||||||||||||
Db 1 IVGGWECEKHSQPWQVAVWSHGWAHCGGVLVHPQWVLTAAHCLKKNSQVWLGRHNLFEPE 60
Qy 85 DTGQRVPVSHSFPHPLYNMSLLKHQSLRPDEDSSHDLMLLRLSEPAKITDVVKVLGLPTQ 144
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTGQRVPVSHSFPHPLYNMSLLKHQSLRPDEDSSHDLMLLRLSEPAKITDVVKVLGLPTQ 120
Qy 145 EPALGTTCYASGWGSIEPEEFLRPRSLQCVSLHLLSNDMCARAYSEKVTEFMLCAGLWTG 204
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 EPALGTTCYASGWGSIEPEEFLRPRSLQCVSLHLLSNDMCARAYSEKVTEFMLCAGLWTG 180
Qy 205 GKDTCGGDSGGPLVCNGVLQGITSWGPEPCALPEKPAVYTKVVHYRKWIKDTIAANP 261
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GKDTCGGDSGGPLVCNGVLQGITSWGPEPCALPEKPAVYTKVVHYRKWIKDTIAANP 237
More importantly, the tested immunogenic fragment is present in the disclosed sequence, shown in the alignment above in bold.
Bouquin taught methods for expression proteins on the surface of cells, e.g. for selecting cells expressing a desired level of a polypeptide of interest. See abstract. Bouquin taught that for such screening purposes, the protein comprises a cell membrane targeting signal which is normally positioned at the carboxy terminus of the protein, and that a preferred targeting signal is a GPI anchoring peptide. See page 19, lines 24-29. Bouquin taught that many GPI anchors were known in the art, and that suitable ones included the human placental alkaline phosphatase GPI (disclosed as SEQ ID NO: 7 and comprising instant SEQ ID NO: 5). See paragraph bridging pages 19-20. Bouquin’s SEQ ID NO: 7 aligns with instant SEQ ID NO: 5 as shown below:
SEQ ID NO 7
LENGTH: 45
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: modified GPI anchor
Query Match 100.0%; Score 157; Length 45;
Best Local Similarity 100.0%;
Matches 32; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TTDAAHPGRSVVPALLPLLAGTLLLLETATAP 32
||||||||||||||||||||||||||||||||
Db 14 TTDAAHPGRSVVPALLPLLAGTLLLLETATAP 45
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to have utilized the nucleic acid construct of Ring that is meant to express any POI fused to a GPI anchor, and encoded the hKLK2 full-length or fragment as the POI, by utilizing Tindall’s disclosed hKLK2 sequence that aligns with instant SEQ ID NO: 4, to express the same as a fusion protein with a GPI anchor sequence, taken from Bouquin disclosed SEQ ID NO: 10 at its 3’-end. One would have been motivated to do so because Brittingham show the significance of hKLK2 as the antigenic stimulus for creating their CAR, and also to take advantage of the increased immunogenicity that occurs upon creating such a fusion of a protein with GPI, as taught by Brown. Doing so would have been no more than substituting one prior art element for another according to known methods to yield predictable results (see MPEP 2143(I)(B)) as the GPI of Bouquin would have been reasonably expected to display the KLK2 peptide of Tindall in the manner disclosed by Ring.
Thus, Ring in view of Brittingham, Brown, Tindall, and Bouquin make instant claims 1 - 3, 5, 12 - 13, and 15 - 17 prima facie obvious.
Regarding claims 4 and 6 - 7, Ring in view of Brittingham, Brown, Tindall, and Bouquin make a recombinant nucleic acid construct comprising a first sequence encoding hKLK2 or a fragment thereof and a second nucleic acid sequence encoding a GPI positioned 3’ to the sequence encoding hKLK2, wherein the first nucleotide sequence comprising the amino acid sequence of human KLK2 comprises SEQ ID NO: 4 and a second nucleotide sequence encoding a glycosylphosphatidylinositol (GPI) attachment sequence comprises the amino acid sequence of SEQ ID NO: 5, and wherein the hKLK2 fusion protein is capable of being expressed on the surface of a cell as a membrane-anchored protein, obvious.
With respect to the nucleotide sequence encoding kallikrein-2 comprises the nucleotide sequence of SEQ ID NO: 1 or a fragment thereof, as required by claim 4, Tindall did not disclose a nucleic acid sequence encoding the disclosed peptides. However, it would have been obvious to have made such a sequence, as discussed above, and all nucleic acid sequences that can encode the peptide of Tindall would have been recognized by those of skill as functional equivalents absent evidence of secondary considerations. Accordingly, all possible sequences encoding the peptide(s) of Tindall were obvious equivalents of each other, including a corresponding fragment of instant SEQ ID NO: 1.
With respect to the GPI attachment sequence is from human placental alkaline phosphatase, as required by claim 6, Bouquin taught that many GPI anchors were known in the art, and that suitable ones included the human placental alkaline phosphatase GPI (disclosed as SEQ ID NO: 7 and comprising instant SEQ ID NO: 5).
Thus, the invention of claims 1 - 7, 9, 12 - 13, and 15 – 17 made prima facie obvious by Ring, Brittingham, Brown, Tindall, and Bouquin, also makes instant claims 4 and 6 - 7 prima facie obvious.
Claims 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Ring (Ring et al., US 20180037898 A1), Brittingham (Brittingham, CA 3148735 A1, published 4-2-2021), Brown (Brown, Abstract, Current Opinion in Immunology, Volume 5, Issue 3, 1993, Pages 349-354), Tindall (Tindall et al., US 5516639), and Bouquin (WO2005073375) as applied to claims 1 - 7, 9, 12 - 13, and 15 – 17 above, and further evidenced by Gao (Gao et al., US 20060142192).
Ring in view of Brittingham, Brown, Tindall, and Bouquin make a recombinant nucleic acid construct comprising a first sequence encoding hKLK2 or a fragment thereof and a second nucleic acid sequence encoding a GPI positioned 3’ to the sequence encoding hKLK2, wherein the first nucleotide sequence comprising the amino acid sequence of human KLK2 comprises SEQ ID NO: 4 and a second nucleotide sequence encoding a glycosylphosphatidylinositol (GPI) attachment sequence comprises the amino acid sequence of SEQ ID NO: 5, and wherein the hKLK2 fusion protein is capable of being expressed on the surface of a cell as a membrane-anchored protein, obvious.
Regarding claim 8, and the requirement that the GPI attachment sequence comprises instant SEQ ID NO: 2, Bouquin did not teach a nucleotide sequence encoding instant SEQ ID NO: 5 that comprised instant SEQ ID NO: 2. However, any nucleic acid sequence that can encode the amino acid sequence of instant SEQ ID NO: 5 is considered to have been obvious in view of Bouquin’s disclosure of instant SEQ ID NO: 5 and the suggestion to express that sequence from a vector. All nucleic acid sequences that can encode the GPI of Bouquin peptide of would have been recognized by those of skill as functional equivalents absent evidence of secondary considerations. Accordingly, all possible sequences encoding the GPI of Bouquin were obvious equivalents of each other, including instant SEQ ID NO: 2. Evidence of this comes from Gao who also disclosed a vector for expressing fusions to human placental alkaline phosphatase GPI, which vector included instant SEQ ID NO: 2. See Gao at [0072], SEQ ID NO: 177, and [0493] (pVAC2-hcytor21-S2), which comprises SEQ ID NO: 177.
The combined use of instant SEQ ID NO: 1 and SEQ ID NO: 2 would result in a sequence that is 90% identical to SEQ ID NO: 3, as required by claim 10, which in turn would translate to a fusion protein of KLK2.
Thus, Ring in view of Brittingham, Brown, Tindall, and Bouquin, evidenced by Gao make obvious instant claims 8 and 10.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Ring et al., (US 20180037898 A1), Brittingham (CA 3148735 A1, published 4-2-2021), Brown (Brown, Abstract, Current Opinion in Immunology, Volume 5, Issue 3, 1993, Pages 349-354), Tindall et al., (US 5516639), and Bouquin (WO2005073375) as applied to claims 1 - 7, 9, 12 - 13, and 15 – 17 above, and further in view of Coljee et al., (US 20140127743).
Ring in view of Brittingham and Brown make a recombinant nucleic acid construct comprising a first sequence encoding hKLK2 or a fragment thereof and a second nucleic acid sequence encoding a GPI positioned 3’ to the sequence encoding hKLK2 and wherein the hKLK2 is capable of being expressed on the surface of a cell as a membrane-anchored protein, i.e., claim 1 obvious.
Further, Ring taught wherein the construct comprises a mammalian promoter driving expression of the encoded protein.
These references did not teach an E1alpha promoter.
Regarding claim 14, Coljee provided general guidance on the expression of recombinant proteins in cells. Coljee taught that such proteins may be expressed from viral vectors such as adenoviral vectors, retroviral vectors ([see 0089]), or an AAV vector ([0104]), and that suitable promoters for driving expression of a recombinant protein included the E1alpha promoter ([0105]-[0106]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to have utilized an E1alpha promoter to drive expression of the protein encoded by the construct resulting from the combination of Ring, Brittingham, and Brown. Doing so would have been no more than substituting one prior art element for another according to known methods to yield predictable results (see MPEP 2143(I)(B)).
Thus, Ring, Brittingham, Brown Tindall, and Bouquin in view of Coljee make instant claim 14 prima facie obvious.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Subject Matter Free of the Prior Art
As explained in MPEP § 2131, subsection III, A generic disclosure will anticipate a claimed species covered by that disclosure when the species can be "at once envisaged" from the disclosure. Thus, while the cited references make obvious the various polynucleotides to combine to achieve the desired functions (expressing a KLK2 fusion protein on the cell membrane), the exact sequence as required by claim 11 of the instant application cannot be at once envisaged.
The sequence bearing SEQ ID NO: 3 is free of the prior art of record. Therefore, claim 11 is allowable.
Response to Arguments
Applicant's arguments filed 11/05/2025 have been fully considered but they are not persuasive.
I. Applicant addresses the 112a written description rejection at pages 12 - 13 of the response.
Applicant asserts:
1. specification provides explicit nucleotide and amino acid sequences (SEQ ID NOs: 1-6).
2. and demonstrates their functionality in detailed experimental examples (Figs. 1-10).
3. amendments limit the scope of the"90% identity" language to conservative substitutions that retain GPI anchoring and surface expression activity, thereby correlating structure with function.
This is unpersuasive because the new ground of rejection does not:
1. include independent claim which has been amended suitably to overcome the rejection.
2. while the specification provides explicit nucleotide and amino acid sequences, it does not do so for fragments thereof language in the dependent claims.
3. the amendment of conservative substitutions… is unsupported by the specification therefore, has not overcome the rejection.
II. Applicant addresses the 103 rejection over Ring in view of Brittingham and Brown at page 13 of the response.
Applicant asserts
Ring is generic, it does not specifically teach or suggest fusing GPI anchors to secreted serine proteases such as KLK2.
Brittingham teaches CAR-T activity against VCaP cells that naturally express KLK2 but not DU145 cells that do not express surface KLK2. This Applicants assert, demonstrates that the field was lacking a model system to study KLK2-targeting agents outside of VCaP. By making DU145 and PC3 cells that stably express KLK2 on their surface, Applicants provide a technical advance not taught or suggested by Brittingham.
Brown is a review article on signaling by endogenous GPI proteins in T cells; provides no guidance that a secreted enzyme like KLK2 could be engineered for membrane localization.
Reliance on Brown as a motivator amounts to hindsight reconstruction.
This is unpersuasive because:
Contrary to Applicant’s assertion, Ring is not generic. Ring provides a working example of fusing an antibody to a GPI anchor. Antibodies are secreted proteins. See Ring Example 4: Yeast Surface Display of Human Antibody Libraries, [0152] onwards.
Brittingham provides the motivation to pursue exactly what is in instant application. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., DU145 and PC3 cells that stably express KLK2 on their surface) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As Applicant concedes, Brown provides motivation for GPI anchoring, as seen from endogenous proteins with GPI anchors; this guidance renders obvious the fusion of GPI anchors on to proteins that generally don’t express on surfaces of cells.
In fact, Brittingham and Brown provide the “therapeutic context” for pursuing instant studies. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, there had been ample suggestion in the prior art that the claimed method would have worked. See PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007). Applicants have not highlighted any additional effort or skill needed to practice the claimed invention other than that already suggested by the references cited.
III. Applicant asserts the instant application demonstrates unexpected results at page 14 of the response.
This is unpersuasive because:
The demonstrated results are expected when interpreted in view of the prior art. While Applicants have provided useful experimental validation of preparing fusion proteins in the context of prostate cancer cell lines, this good science is not translatable into patentability, as the following quote from the MPEP suggests: The Federal Circuit concluded that "[g]ood science and useful contributions do not necessarily result in patentability." Id. at 1364, 83 USPQ2d at 1304, MPEP 2145, Example 1.
IV. Applicant asserts that references applied towards dependent claims do not make any specific teaching or suggestion related to KLK2, GPI anchors, or prostate cancer targeting at end of page 14 of the response.
Again, this is unpersuasive because:
The claimed construct is obvious over the prior art relied upon because the references contain a detailed enabling methodology to make a similar construct, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful. By extrapolation, one of ordinary skill in the art would have expected to make a construct comprising a GPI anchor fused to KLK2 as well.
Applicants have not provided any arguments rendering the references invalid for the reasons the art was applied nor have they provided any evidence showing there was no reasonable expectation of success.
None of Applicant’s four reasons listed above is dispositive; the rejection is maintained. The rejections cited in this Office Action have been rewritten to address amendments.
Conclusion
Claim 11 is allowed, for reasons communicated in prior Office Actions and reiterated in Subject Matter Free of the Prior Art of Record above.
Claims 1 – 10 and 12 – 17 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635