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.
Election/Restrictions
Applicant's election with traverse of SEQ ID 9 in the reply filed on 2 Oct, 2025 is acknowledged. The traversal is on the ground(s) that the claims have unity of invention. This is not found persuasive because the election/restriction requirement merely required an election of species.
The requirement is still deemed proper and is therefore made FINAL.
Applicants have elected SEQ ID 9. A search was conducted for this invention, and it was determined to be novel an unobvious over the prior art. The closest prior art found was Inui (WO 2013118502, cited by applicants). This reference describes a sequence with two of the three mutations of SEQ ID 9, the C45A and C147A, but not the M72W mutation. While Skerra et al (WO 20150031618) discusses mutations in this part of the sequence to add binding capacity to the molecule (paragraph 6), neither of these references, or any other reference found, discusses the M72W mutation of SEQ ID 9. Thus, this embodiment is both novel and unobvious over the prior art.
Following Markush practice, the search was expanded to independent claim 1, there being no Markush claim, and references were found that rendered the claim obvious. As a result, claims 1-3 and 8-10 have been examined and claims 4-7 have been withdrawn from consideration.
Claims Status
Claims 1-12 are pending.
Claims 4-7 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 2 Oct, 2025.
Examiner’s Note
“Capsule protein” has many possible interpretations; the Merriam Webster dictionary lists several that may apply. However, consistent with how the term is used in the specification, it is interpreted as a lipocalin type prostaglandin D synthase structure that can encapsulate a drug material.
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.
first rejection
Claims 1-3 and 8-10 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue at question is if a given amino acid in β strand D is a barrier amino acid.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants have defined a barrier amino acid as an amino acid capable of reducing the aperture area of the open mouth 10 of fig 3 (paragraph 26). It is noted that the mutation to include a barrier amino acid should not destroy the structure (paragraph 27). The only example described is an M72W mutation (paragraph 54), which reduced the rate of diffusion of the drug out of the complex (fig 10), but it is not demonstrated that this is due to a reduction of the aperture size.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicant is claiming an enzyme modified to reduce the size of the opening in a barrel structure. This is a functional requirement that the modified sequence 1) fold into a barrel structure and 2) fold into a structure with a reduced aperture compared to the unmodified structure. However, applicants have not described what structural features are required to meet these functional limitations. A person of skill in the art would not know what aromaticity/sequence/charge requirements are necessary to meet this functional requirement. In essence, applicant has defined their invention by function. That is not sufficient to meet the written description requirement.
As of applicant’s priority date, it was not possible to determine the tertiary structure of a polypeptide from its primary sequence. Howes (C&EN, issue of 1 Dec, 2020) discusses the solution of this problem (title). Prior to this software, even the best prediction programs could not match the ones obtained by structural biology experiments (1st page, 3d paragraph). This is a problem that has bedeviled researchers for 50 years, and was not solved before until the end of 2020 (1st page, 1st paragraph).
Betts et al (Prot. Sci. (2004) 13 p2291-2203) discusses β-sheet mutants (abstract). Replacing Phe residues with bulky Val or Leu affected folding, and that it was necessary for structure that the hydrophobic residues be buried (abstract). Note that if the residues are buried, they are not sticking out into the medium to shrink the aperture.
Similar effects are noted in general, measuring protein activity of mutants. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants have one example of a mutated D-strand that reduces the rate of diffusion of a drug out of the barrel by about 10 fold (fig 10). Applicants have not demonstrated that reduction in the release rate is due to the reduction of the size of the opening. This seems to be a very large reduction compared to the size of the side chains (methionine vs. tryptophan). That suggests a different mechanism, such as direct π binding between the side chain and the drug. Given that, as of applicant’s priority date, it was not possible to predict how a mutation would change the structure of a polypeptide, that mutations similar to those suggested by applicants are known to cause aberrant folding in a different β-sheet containing polypeptide, and that random mutations are likely to abrogate function (suggesting a structural change), an artisan in this field would not know which D-strand mutants contained a barrier amino acid. Thus, the claims lack written description.
second rejection
Claim 3 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would know if a sequence was a targeting peptide.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants describe a small number of known targeting peptides, specifically NGR, RGD, CRGDK (paragraph 31), KLP, NVVRJQ, and FQHPSFI (paragraph 32), all of which are previously known in the art.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicant has claimed a polypeptide with a targeting peptide attached. There is no definition of targeting peptide, so it is interpreted as a peptide that binds to a (unspecified) target, consistent with the plain language of the terms. This requires that the sequence bind to a given target, which is not specified by any claim. However, applicant has not disclosed what structural features are required for this functional limitation. A person of skill in the art, armed with applicant’s disclosure, would not know what sequence/hydrogen bonding capability/hydrophobicity is required to meet this functional limitation. In essence, applicant has defined a portion of their invention by function. This is not sufficient to meet the written description requirement.
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, several years after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
This is emphasized by Alteen et al (PNAS (2023) 120(42) e2303690120). Alteen et al used phage display, a high throughput screening technique, to identify peptide sequences that bind to a given target (abstract). In other words, well after applicant’s priority date, a person of skill in the art needed to screen for a targeting peptide; it was not self evident from the target with current technology.
(d) representative number of samples: Applicants describe a small number of previously known targeting sequences. Given that the target is not specified, that a targeting sequence for a given target cannot be determined a priori, nor is it possible to reliably modify a sequence and retain targeting, this is insufficient support for any polypeptide sequence that targets any ligand. Thus, the claim lacks written description.
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.
Claims 1-3 and 8-10 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, and claims dependent on it, requires a mutation in the D-strand of human lipocalin type prostaglandin D synthase. However, it is not clear what the mutant is compared to. For example, a human variant with a Q75L mutation (compared to SEQ ID 1 of the examined claims) has been found in an ovarian cancer patient (US 20060199180, SEQ ID 252). As there are multiple human lipocalin type prostaglandin D synthase sequences, with variations on the D-strand, it is not clear what is the base sequence used for comparison.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 and 8-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Inui (WO 2013118502, cited by applicants) with evidentiary support by Macina et al (US 20060199180). Note that Inui is in Japanese. A machine language translation of this reference was used for this rejection, and citations to locations in this reference refer to the machine translation.
Inui describes a protein with a barrel structure containing a pocket into which a drug can be stored, which can be sealed with a disulfide bond (paragraph 10), specifically, a deactivated lipocalin type prostaglandin D synthase (paragraph 11). To open and close the structure, tryptophans at positions 34 and 92 are modified to Cys residues to open and close the pocket (paragraphs 21-23), relevant to claim 2. The drug complex can be lyophilized without damage (paragraph 25, relevant to claim 9) and can have a target protein attached at either end (paragraph 26), relevant to claim 3. Diazepam loaded material was administered orally to mice (paragraph 53), interpreted as a food material, relevant to claims 8 and 10. This sequence also had a C48A mutant to deactivate the enzyme (paragraph 31), relevant to claim 1. As evidenced by Macina et al, an ovarian cancer produced mRNA that corresponds exactly to the sequence of Inui, save that it does not have the inactivating mutation, and has a Q75L mutation (numbering of SEQ ID 1 of the examined application) (compare SEQ ID 252 of Macina et al to table 1 of Inui) (paragraph 455 and associated table of Macina et al). This means that, compared to the sequence of Macina et al, the sequence of Inui has a mutation on the D strand which has every structural requirement that applicant has stated is required to be a barrier amino acid residue, so it inherently must be.
Inui describes a sequence of human lipocalin type d prostaglandin D synthase, with a deactivating mutation (C to A) at the active site and (compared to Machina et al) a mutation in the D strand that inherently will be a barrier amino acid, anticipating claim 1.
Inui describes two tryptophans mutated to cystines, for the same purpose as applicant’s mutations nearby, anticipating claim 2.
Inui describes attaching a targeting peptide to either end of the sequence, anticipating claim 3.
Inui describes the material with a drug loaded into it, administered to mice (i.e. pharmaceutical formulation), anticipating claim 8.
Inui describes lyophilizing the material, anticipating claim 9.
Inui describes oral administration of the material, which is interpreted as anticipating claim 10.
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