Alr 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 a). size exclusion chromatography (SEC) and b). AAV9 capsid in the reply filed on 7/24/2026 is acknowledged.
Claims 1, 5-9, 17, 19-20, 32-33, 37, 39, 42 and 54-56 read on the elected species of a). size exclusion chromatography (SEC) and b). AAV9 capsid are considered.
Claims 1, 5-9, 17, 19-20, 32-33, 37, 39, 42, 54-56, 61, 63 and 65 are pending.
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.
Claims 1, 5-9, 17, 19-20, 32, 33, 37, 39, 42 and 54-56 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite and confusing in that it fails to point out or define what is included or excluded by the claim language of empty or partial capsid. This type of claim(s) is an omnibus type of claim(s). In the instant case, it is unclear if the claimed method is used for determining a presence of a full empty capsid or partial empty capsid in coding sequence level of in protein expression level. , i.e. is the capsid only contains help of the gene of the capsid of viral gene or the capsid comprises some other gene integrated into the capsid of the viral gene, therefore, the endogenous capsid maybe completely full without any integrated foreign gene inserted to or partially occupied with a foreign gene or it is just help of the gene of capsid protein of AAV. Please clarify.
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, 5-9, 17, 19-20, 32, 37, 39, 42 and 54-56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for determine a presence of empty capsids and separating said empty capsid from an unpurified mixture composition comprising both an interested gene packaged and non-packaged into the empty capsid of recombinant adeno-associated virus (rAAV) particles ,using a size exclusion chromatography made by particular particles selected with 3 pm to about 10 pm in diameter and also with pores of 100 k to 1000 k in size via a). measuring and monitoring the UV absorbance from 250 nm to 270 nm (A250-27o) and from 220 nm to 240 nM (A220-240) of the eluate, c) plotting chromatograms of the A250-27o and A220-240 of the eluate, d) integrating the area under the peaks representing the rAAV particles for the A250-270 and A220-240 plots, wherein the peak area ratio at A250-27o and A220-240 (PA260/PA230) to indicate the presence of the presence of with full empty capsid from fully packed capsid with an interested gene carried by a rAAV, wherein a PA260/PA230 ratio equal to the full capsid to the empty capsid ranging from 1:0 to 0:1; whoever, it does not reasonably provide enablement for using any kind of chromatography or even a SEC with any side in diameter and pore size. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of an enablement or scope of enablement is whether one skilled in the art could make and use the claimed invention from the disclosure in the application coupled with information known in the art would render undue experimentation (See United States v. Theketronic Inc., 8USPQ2d 1217 (fed Cir. 1988). Whether undue experimentation is required is not based upon a single factor but rather a conclusion reached by weighting many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in re Wands, 8USPQ2d 1400 (Fed. Cir. 1988), which are set forth below:
1). Nature of invention; 2). Scope of claims; 3). State of art; 4). Unpredictability; 5). Level of skill in the art; 6). Number of working examples and 7). Amount of guidance presented in the specification.
The nature of invention is directed to a method using a SEC with particular molecular size and pore in the purification column with a UV monitoring spectrum to monitor the separating process of the full packaged capsid protein of rAAV particles and empty capsid in an eluate of the chromatography; by loading and separating the mixture via monitoring and measuring the UV absorbance at about 250 nm to about 270 nm (A250-27o), and also 220 nm to about 240 nM (A220-240) followed by plotting the eluted rAAV changes during the chromatograms of the selected UV A250-27o and A220-240 and then integrating the area under the peaks representing the rAAV full particles for the A250-270 and empty particle at A220-240 plots, wherein the peak ratio at A250-27o to A220-240 (PA260/PA230) is indicative of the presence of empty and/or partial capsids in the composition read from 1.0 to 0.1 or selected from the group consisting of 1:0, 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0:4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8, 0.1:0.9, and 0:1 based on three or more rAAV preparations comprise known ratios of full capsids to empty capsids of any one of the rAAV.
However, the scope of the claims read on using any or all chromatographic columns. But the specification only provide one example using the SEC equipped with particular particles selected from 3 pm to about 10 pm in diameter and also with pores of 100 k to 1000 k in size.
The stat of art teaches that chromatographic analysis or purification columns comprise several kinds, where each of them functions in different way for the separations. For instance, there are four main types of chromatography apparatus and systems widely used in laboratories, matched to the primary separation techniques. Such as Gas Chromatography (GC) Apparatus: which Uses an inert carrier gas mobile phase, an injector port, a specialized column, a temperature-controlled oven, and a detector (like a flame ionization or mass spectrometer detector) to analyze volatile compounds; High-Performance Liquid Chromatography (HPLC / UHPLC) Systems: Uses high-pressure solvent pumps, sample injectors or autosamplers, packed liquid chromatography columns, and optical or mass spectrometry detectors enclosed in a standalone unit; Thin-Layer Chromatography (TLC) Setup: Uses simple glass or metal development chambers and flat plates coated with a solid stationary phase like silica gel for basic manual separations; Paper Chromatography Equipment: Uses a simple glass tank or jar holding a solvent mobile phase and specialized filter paper strips acting as the stationary phase.
However, the chromatography can be classified based on the separation mechanisms set forth below:
1. Size Exclusion Chromatography (SEC) / Gel Filtration
Mechanism: Separation based on molecular size.
Principle: Larger molecules cannot enter the pores of the stationary phase and elute first; smaller molecules enter pores and take longer to elute.
Stationary phase: Cross-linked polymer beads (e.g., Sephadex, Sephacryl).
Applications: Protein purification, desalting, analysis of macromolecules
2. Adsorption Chromatography
Mechanism: Separation based on adsorption affinity.
Principle: Components bind differently to the surface of the stationary phase (e.g., silica, alumina).
Types: Normal phase (polar stationary phase, non-polar mobile phase) and reverse phase (non-polar stationary phase, polar mobile phase)
3. Partition Chromatography
Mechanism: Separation based on solubility in two immiscible phases.
Principle: Components distribute between the mobile and stationary phases differently.
Example: Liquid–liquid partition chromatography.
4. Ion Exchange Chromatography
Mechanism: Separation based on charge.
Principle: Charged species bind to oppositely charged functional groups on the stationary phase.
Types: Cation exchange (positively charged groups) and anion exchange (negatively charged groups)
5. Affinity Chromatography
Mechanism: Separation based on specific molecular recognition.
Principle: Target molecules bind to a ligand immobilized on the stationary phase.
Applications: Protein purification, antibody separation
6. Hydrophobic Interaction Chromatography (HIC)
Mechanism: Separation based on hydrophobicity.
Principle: Hydrophobic molecules bind to hydrophobic ligands on the stationary phase and elute with increasing salt concentration.
7. Chiral Chromatography
Mechanism: Separation based on stereochemistry.
Principle: Chiral stationary phases differentiate between enantiomers.
8. Capillary (Open Tubular) Columns
Mechanism: Separation based on partitioning or adsorption in a coated capillary.
Principle: Common in gas chromatography and some liquid chromatography modes
Apparently, different chromatographic columns use different mechanisms . Hence the UV monitoring spectrums would not be the same. So, it is unpredictable for using any or all chromograph columns and same PA260/230 UV WAVELGTH to determine the empty or full capsid or a rAAV particle in a capsid purification or monitoring the process successfully.
. The Level of skill in the art to practice the claimed method is above PhD level and sufficient numbers of working examples are missing from the disclosure and so and nether the amount of guidance presented in the specification that is missing.
Given the above analysis of the factors which the courts have determined are critical in asserting whether a claimed invention is enabled, it must be considered that the skilled artisan would have to conduct undue and excessive experimentation in order to practice the claimed invention.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/Primary Examiner, Art Unit 1671
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