OK, this is the reason the examiner gave. I got this from one of the documents that HDG provided on the folder that contains all the info he knows, so big thank you to him and on a personal note, missing him on the message board. I hope he can be back as soon as possible
This is the document for those that want to read it:
The prior art does not teach the administration of ethyl-EPA to patients having TG levels between 500 and 1500 mg/dl (very high), as such there is no anticipation. However, the prior art teaches that: 96% pure ethyl-EPA has been administered to patients with TG levels between 150- 499 mg/dl (borderline high/high) in order to lower TG levels in amounts that range from 1.8 g per day up to 4.0 per day and for periods of time ranging from a few weeks up to two years (see non-final rejection dated 03/02/2012, pages 4 through page 7, first paragraph). in every case a substantial reduction of TG levels was observed. The prior art also teaches that the administration of a mixture of ethyl-EPA and DHA (also known as Lovaza or Omacor) to patients with TG levels above 500 mg/dl (very high). The results show a dramatic reduction in TG levels (about 50%). Based on these references it was concluded that it wil be obvious to treat patients having TG above 500 mg/dl with 96% pure ethyl-EPA (see pages 7 and 8 of the non-final rejection dated 03/02/2012). Regarding the preamble statement: lowering apolipoprotein B (Apo-B), it was concluded that it merely recites the purpose of a process made obvious by the prior art (the administration of 96% pure ethyl-EPA to patients having TG levels above 500 mg/dl) (see page 8 of the non-final rejection dated 03/02/2012).
However, Applicant was able to overcome the above 103 obviousness rejection by showing: 1- Unexpected results, and 2- Long felt unmet medical need.
1- Unexpected results: Applicant was able to demonstrate that under the specific conditions of the instant claims a significant reduction (8.5%) of Apo-B levels in the patients being treated was observed. This reduction of Apo-B was observed at the 4 g per day dose bot not at the 2 g per day dose (see MARINE trial, Bays et. al. Am. J. Cardiol. (2011) 108:682- 690, Figure 3 on page 684). Apo-B is a very important marker for coronary heart disease (see Bays’ declaration dated 05/16/2012, topics 28 through 32 on pages 8 and 9; see also Bays et. al. Am. J. Cardiol. (2011) 108:682-690, page 689, left column, second paragraph). The prior art is either silent or teaches that there is no statistically significant change in Apo-B levels when patients with TG levels less than 150 mg/dl or between 150-499 mg/dl are treated with either 96% pure ethyl-EPA or a mixture of ethyl-EPA and DHA, or when a mixture of ethyl-EPA and DHA was administered to patients with TG levels above 500 mg/dl (see item 25 on page 6 and Table 1 of the Bays’ declaration dated 05/16/2012; see also Table A on page 15 of Applicant’s response dated 01/13/2012). Applicant also presented convincing arguments (see Bays' declaration dated 05/16/2012, items 10 through 24 on pages 2 through 6) against the three references presented by the Examiner (Connor et. al., Fisher et. al. and Park et. al.) regarding the predictability of lowering Apo-B with 96% pure ethyl EPA in patients with TG levels above 500 mg/dl (see non-final rejection dated 03/02/2012, pages 20-23). Basically, the Connor reference evaluated oil” which contains approximately about 10% of EPA and a complex mixture of omega 3 and other fatty acids in individuals with TG levels below 500 mg/dl; as such the results of Connor cannot be correlated with the effect on Apo-B levels that the administration of 96% pure ethyl-EPA wil have in patients with TG above 500 mg/dl. The Fisher reference is an in vitro study showing the effect of pure ethyl-EPA in reducing Apo-B secretion from rat hepatocytes. However, as pointed by Dr. Bays (see items 18, 19 and 20 on page 5 of the declaration dated 05/16/2012), there are several organs that, besides the liver, that metabolize lipids, and there is evidence that in human hepatoma cells (HEP G2) EPA significantly increased apolipoprotein B (Arrol et. al.). Finally the Park reference, contrary to previous Examiner’s conclusion, emphasizes Applicant’s point that at time zero ethyl- EPA did not decrease fasting Apo-B levels compared to placebo. In summary, based on the above prior art it was completely unexpected to observe an 8.5% decrease in Apo-B when patients with TG levels above 500 mg/dl were administered 4 g of 96% pure ethyl-EPA. Also, based on the fact that the MARINE trial (Bays et. al. Am. J. Cardiol. (2011) 108:682-690) shows the criticality of the 4 g per day dose, as opposed to the 2 g per day dose wherein no Apo-B effect was observed, and based on the importance of lowering Apo-B in these patients, it is concluded that Applicant has effectively shown unexpected results for his invention.
2- Long felt unmet medical need. The prior art teaches only two other drugs that have been approved for the treatment of triglycerides in patients with TG above 500 mg/d (very high)l: 1- Lovaza (a mixture of EPA and DHA), and 2- Triplix (a fenofibric acid). Both treatments lower TG significantly (50-60%), however both treatments also raised LDL-C (the bad cholesterol) significantly (about 50%) (See Lovaza package and Triplix Package; see also Table 1 on page 13 of Applicant’s arguments dated 09/21/2011). According to Dr. Weintraub there is a need for a treatment for patients with TG above 500 mg/dl (very high) that not only reduces the level of TG but also does not increase LDL-C which is associated, like Apo-B, with an increase in cardiovascular diseases (see applicant’s response dated 09/21/2011, pages 14-21). When combined with the fact that the levels of Apo-B are also decreased, this treatment: the administration of 4 g daily of 96% pure ethyl EPA for a period of at least 12 weeks to patients with TG above 500 mg/dl that are not on concomitant lipid altering therapy, becomes the only one available that, besides significantly lowering TG levels, also does not increase LDL-C levels and decreases apolipoprotein B levels, two important markers strongly associated with increase in cardiovascular diseases. The above justifies the allowance of the instant claims in their full scope. Page 9 Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled on Statement of Reasons for Allowance.”
