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 .
Applicants' arguments, filed November 18, 2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims
Claim Rejections - 35 USC § 103 – Obviousness (Maintained Rejections)
1) Claims 2-3, 6-7, 11-13 and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over Phelps (WO 2004028243) in view of Hawkins et al. (J. Card. Surg. 2016) in further view of Kollmann (Allergy 2017).
Phelps discloses porcine animal, tissue, organ, cells and cell lines, which lack expression of functional alpha 1,3 galactosyltransferase (alpha 1,3GT). These animals, tissues, organs and cells can be used in xenotransplantation and for other medical purposes (Abstract). The invention provides the complete inactivation of both alleles of the alpha 1,3 galactosyltransferase gene in pigs, thus overcoming this longstanding hurdle and making xenotransplantation a reality. Eliminating the expression of this gene, resulting in a lack of galactose alpha 1,3-galactose epitopes on the cell surface, represents the first and major step in eliminating hyperacute rejection in pig-to-human xenotransplantation therapy. The invention also provides organs, tissues, and cells derived from such porcine animals, which are useful for xenotransplantation. The cells can be administered into a host in order in a wide variety of ways. Preferred modes of administration are topical, transdermal patch, intracardiac, surgical implants, internal surgical paint, catheter and, nasal spray. This meets the limitation of medical product. The materials may also be made into extracellular matrices for medical devices. This would meet the limitation of not directly implanted into a subject.
Phelps differs from the instant claims insofar as they do not disclose the patient population or antibodies to IgE and IgG4.
Hawkins et al. disclose allergy to mammalian meat is increasingly prevalent around the world. Patients develop anaphylactic reactions after eating beef, pork, or lamb. The mammalian meat allergy is to galactose-alpha-1,3-galactose. The alpha-gal oligosaccharide is a blood group structure evolutionarily conserved in most non-primate mammalian species. While ingestion of this antigen is harmless, inoculation by the lone star tick (Amblyomma americanum) induces both an IgG1 and IgE response, and is thought to be the inciting event. As bioprosthetic valves and heparin are bovine or porcine-derived products, alpha-gal allergy may be a significant factor in valve surgery. Two patients at our institution were found to have a history of tick bites, elevated alpha-gal IgE titers, and development of mammalian meat allergy within the last two years (alpha Gal Syndrome). They presented with heart failure symptoms and evaluation demonstrated rapid degeneration of their bioprosthetic aortic valves (Abstract).
It would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to have made a bioprosthetic aortic valve with the cells and tissues of Phelps to treat patients with alpha Gal Syndrome motivated by the desire to avoid an allergic reaction form galactose-alpha-1,3-galactose.
Phelps in view Hawkins et al. differ from the instant claims insofar as it does not disclose IgG4 antibodies.
Kollmann et al. disclose IgG to galactose-α-1,3-galactose (α-gal) are highly abundant natural antibodies (Ab) in humans. α-Gal-specific IgE Ab cause a special form of meat allergy characterized by severe systemic reactions 3–7 h after consumption of red meat. Twenty patients who experienced such reactions and characterized their α-gal-specific IgE and IgG responses in more detail (Background). Meat-allergic patients showed significantly higher α-gal-specific IgG1 and IgG3 Ab than nonallergic individuals, whereas the latter showed significantly higher levels of α-gal-specific IgG4 Ab. Children sensitized to egg and/or milk but tolerating these foods have been shown to display higher levels of allergen-specific IgG4 and higher IgG4/IgE ratios than those with allergic reactions.
It would have been obvious to one of ordinary skill in the art to have used the products and devices of Phelps et al. on patient diagnosed with Alpha Gal Syndrome having IgG4 and IgE antibodies because this patient population would have a lower chance of having an allergic reaction to the product or implant because they have higher levels of IgG4 antibodies as suggested by Kollmann et al.
In regards to claim 22, the compositions would not cause symptoms associated with alpha-gal-mediated allergic reaction because it does not comprise alpha 1,3-galactosyltransferase.
In regards to the compositions exhibiting premature degradation, the subject would not have an immunogenic response and therefor the composition would not degrade prematurely.
Response to Arguments
The Examiner submits that although Phelps discloses direct transplantation, Phelps also disclose consumer products. Consumer products would include a nasal spray. Phelps also discloses that the resultant cells disclosed therein, lack galactose alpha 1,3-galactose epitopes, which causes allergies to meat. Therefore, it would have been obvious for people having these meat allergies to use products of Phelps because they lack galactose alpha 1,3-galactose epitopes. In regards to the allergies, Hawkins cures this deficiency. Although Phelps does not disclose allergies, it discloses the cause of reactions, galactose alpha 1,3-galactose. Therefore, one would also conclude that these reactions include allergies. In regards to the products, Phelps discloses nasal sprays. The products of Phelps do not comprise the component that causes reactions in subjects with alpha Gal Syndrome. Therefore, it would have been obvious for alpha gal patients to use the products of Phelps. In regards to the “other medical purposes”, Phelps teaches consumer products such as nasal sprays. In regards to not disclosing food allergies, Phelps discloses a lack of galactose alpha 1,3-galactose epitopes on the cell surface, represents the first and major step in eliminating hyperacute rejection in pig-to-human xenotransplantation therapy. Hawkins et al. disclose allergy to mammalian meat and patients develop anaphylactic reactions after eating beef, pork, or lamb. The mammalian meat allergy is to galactose-alpha-1,3-galactose. Therefore, it would have been obvious for patients of Hawkins to use the products of Phelps because they don’t have the component that causes the meat allergy. In regards to the correlation between HAR and galactose-alpha-1,3-galactose reaction, they both are related to the presence of galactose-alpha-1,3-galactose. Therefore, it would have been obvious to use or make compositions with the components of Phelps because they do not have galactose-alpha-1,3-galactose. Products made from the components would not cause an allergic reaction. Therefore, it would have been obvious to combine the teachings of Phelps with Hawkins. It is not required for Hawkins to teach or suggest all the limitations of the instant claims. Phelps teaches products without galactose-alpha-1,3-galactose. Hawkins teaches galactose-alpha-1,3-galactose causes meat allergies. Therefore, one of ordinary skill in the art would reasonably conclude that a patient with a meat allergy caused by galactose-alpha-1,3-galactose would benefit from using the products of Phelps. In regards to the Neu5Gc, this is remedied by Duvaux et al. In regards to relying on Hawkins, Hawkins teaches the allergy is due to galactose-alpha-1,3-galactose. Therefore, one would reasonably conclude that products without galactose-alpha-1,3-galactose would be safe for those with alpha Gal Syndrome, when one is diagnosed with alpha Gal Syndrome regardless of when one is diagnosed. Those diagnosed with the syndrome would avoid products comprising galactose-alpha-1,3-galactose. Just as in the case with one with peanut allergies, they would avoid items with peanuts. In regards to the bioprosthetic valves, based on the combined teachings, one would be motivated to replace a bioprosthetic valve with the materials of Phelps because they do not comprise galactose-alpha-1,3-galactose and therefore would not cause an allergic reaction. Kollmann cures the deficiencies of Phelps and Hawkins by disclosing the relationship of the antibodies to allergic reactions. One would be motivated to use the products of Phelps in view of Hawkins on a patient population diagnosed with Alpha Gal Syndrome having IgG4 and IgE antibodies because this patient population would have a lower chance of having an allergic reaction to the product or implant because they have higher levels of IgG4 antibodies as suggested by Kollmann et al. Further, as Applicant asserts, those with alpha-Gal don’t develop the allergies until a few years. The claims recite reducing the risk or severity. Therefore, using products without galactose-alpha-1,3-galactose would reduce the risk or severity of an allergic reaction. Therefore, it would have been obvious to have used the products of Hawkins on this population to ensure an allergic reaction didn’t occur further in the future. Therefore, a reason was articulated based on the combined teachings of the references. The rejection is based on the combined teachings and not the references individually. Therefore, one reference is not required to teach all the limitation of the instant claims.
2) Claims 4, 14 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Phelps (WO 2004028243) in view of Hawkins et al. in further view of Kollmann (Allergy 2017) in further view of Duvaux et al. (WO 2016059161).
Phelps in view of Hawkins and Kollmann is discussed above and differs from the instant claims insofar as it does not disclose reduction of the expression of N-glycolneuraminic acid (Neu5Gc).
Duvaux et al. disclose polyclonal antibodies (proteins) directed against at least one non-human biological pathogen, or against at least one molecule derived from said pathogen, towards a human or a non-human animal organism, wherein the said polyclonal antibodies are devoid of an antigenic determinant selected in a group comprising (i) N-glycolneuraminic acid (Neu5Gc) and/or (ii) a-l,3-galactose, and their use as a medicament. The pathogens include bacteria, parasites, and toxins. The present invention also pertains to a polyclonal antibody or a composition such as described above for its use for preventing and/or treating a severe infection including Colorado tick fever. Animals include pigs, goats and horses (page 27, lines 17-23) (instant claims 3 and 13). A method for producing polyclonal antibodies, or a composition comprising polyclonal antibodies comprises the steps of: a) providing a genetically altered non-human mammal lacking a first gene selected in a group comprising (i) a gene encoding a functional cytidine-5'- monophosphate N-acetyl neuraminic acid hydrolase (CMAH) and (ii) a gene encoding a functional a-(l,3)- galactosyltransferase (alpha ,3GT, GGTA1 or GT1); b) immunizing the said genetically altered non-human mammal against at least one non-human biological pathogen(s), towards a human or a non-human animal organism, preferably towards a human organism, or against at least one molecule(s) derived from said pathogen(s); and c) collecting the antibodies contained in a body fluid of the said genetically altered non- human mammal of step b). In a preferred embodiment, the genetically altered non- human mammal lacks the two genes selected in the group characterized by (i) the gene encoding a functional cytidine-5 '-monophosphate N-acetyl neuraminic acid hydrolase (CMAH) and (ii) the gene encoding a functional a-(l,3)-galactosyltransferase (alphal,3GT, GGTA1 or GT1) (meeting instant claims 4 and 14). The compositions include medicaments (page 31, lines 22-25) (meeting instant claim 2).
It would have been obvious to one of ordinary skill in the art prior to filing the instant application to have also removed CMAH in the implants and products of Phelps in view of Hawkins and Kollmann motivated by the desire to further reduce the risk or severity of an alpha-gal-mediated allergic reaction in a subject with alpha Gal syndrome.
Response to Arguments
See Response to Augments above in regards to Phelps, Hawkins and Kollmann. Duvaux cures the deficiencies of by providing motivation to remove CMAH from the products of Phelps when using them on a patient diagnosed or not diagnosed with alpha-Gal Syndrome. Therefore the combination would reduce the risk of severity of an allergic reaction.
Conclusion
Claims 2-4, 6-7, 11-14, and 16-23 are rejected.
Claims 9-10 are withdrawn.
No claims allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEZAH ROBERTS whose telephone number is (571)272-1071. The examiner can normally be reached Monday-Friday 11:00-7:30.
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/LEZAH ROBERTS/Primary Examiner, Art Unit 1612